{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T18:23:19Z","timestamp":1790101399065,"version":"4.0.1"},"reference-count":213,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,1,23]],"date-time":"2018-01-23T00:00:00Z","timestamp":1516665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL81720"],"award-info":[{"award-number":["R01HL81720"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R15HL135699"],"award-info":[{"award-number":["R15HL135699"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>Cardiovascular disease (CVD), including myocardial infarction (MI) and peripheral or coronary artery disease (PAD, CAD), remains the number one killer of individuals in the United States and worldwide, accounting for nearly 18 million (&gt;30%) global deaths annually. Despite considerable basic science and clinical investigation aimed at identifying key etiologic components of and potential therapeutic targets for CVD, the number of individuals afflicted with these dreaded diseases continues to rise. Of the many biochemical, molecular, and cellular elements and processes characterized to date that have potential to control foundational facets of CVD, the multifaceted cyclic nucleotide pathways continue to be of primary basic science and clinical interest. Cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP) and their plethora of downstream protein kinase effectors serve ubiquitous roles not only in cardiovascular homeostasis but also in the pathogenesis of CVD. Already a major target for clinical pharmacotherapy for CVD as well as other pathologies, novel and potentially clinically appealing actions of cyclic nucleotides and their downstream targets are still being discovered. With this in mind, this review article focuses on our current state of knowledge of the cyclic nucleotide-driven serine (Ser)\/threonine (Thr) protein kinases in CVD with particular emphasis on cyclic AMP-dependent protein kinase (PKA) and cyclic GMP-dependent protein kinase (PKG). Attention is given to the regulatory interactions of these kinases with inflammatory components including interleukin 6 signals, with G protein-coupled receptor and growth factor signals, and with growth and synthetic transcriptional platforms underlying CVD pathogenesis. This article concludes with a brief discussion of potential future directions and highlights the importance for continued basic science and clinical study of cyclic nucleotide-directed protein kinases as emerging and crucial controllers of cardiac and vascular disease pathologies.<\/jats:p>","DOI":"10.3390\/jcdd5010006","type":"journal-article","created":{"date-parts":[[2018,1,23]],"date-time":"2018-01-23T13:06:51Z","timestamp":1516712811000},"page":"6","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cyclic Nucleotide-Directed Protein Kinases in Cardiovascular Inflammation and Growth"],"prefix":"10.3390","volume":"5","author":[{"given":"Nathan","family":"Holland","sequence":"first","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jake","family":"Francisco","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Morgan","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5719-3937","authenticated-orcid":false,"given":"Troy","family":"Dennis","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishitha","family":"Gadireddy","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3490-2283","authenticated-orcid":false,"given":"David","family":"Tulis","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, 600 Moye Boulevard, Greenville, NC 27834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e146","DOI":"10.1161\/CIR.0000000000000485","article-title":"Heart disease and stroke statistics-2017 update: A report from the American Heart Association","volume":"135","author":"Benjamin","year":"2017","journal-title":"Circulation"},{"key":"ref_2","unstructured":"World Health Organization (2017, December 18). Cardiovascular Diseases (CVDs) Fact Sheet. Available online: http:\/\/www.who.int\/mediacentre\/factsheets\/fs317\/en\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.coph.2017.03.003","article-title":"Novel protein kinase targets in vascular smooth muscle therapeutics","volume":"33","author":"Tulis","year":"2017","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1016\/j.bbapap.2013.03.010","article-title":"AGC protein kinases: From structural mechanism of regulation to allosteric drug development for the treatment of human diseases","volume":"1834","author":"Arencibia","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Xavier, G.D.S. (2012). Multiple kinase involvement in the regulation of vascular growth. Advances in Protein Kinases, InTech Open Access Publishers.","DOI":"10.5772\/2692"},{"key":"ref_6","first-page":"H328","article-title":"Cimp synthesized by sGC as a mediator of hypoxic contraction of coronary arteries","volume":"307","author":"Chen","year":"2014","journal-title":"Am. J. Physiol."},{"key":"ref_7","unstructured":"Tulis, D.A. (2014). Novel cyclic nucleotide signals in the control of pathologic vascular smooth muscle growth. Cardiovascular Disease ii, iCONCEPT Press, Ltd."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"409","DOI":"10.3389\/fphys.2012.00409","article-title":"Inhibition of vascular smooth muscle growth via signaling crosstalk between AMP-activated protein kinase and cAMP-dependent protein kinase","volume":"3","author":"Stone","year":"2012","journal-title":"Front. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sakuma, K. (2015). Vascular smooth muscle as a therapeutic target in disease pathology. Muscle Cell and Tissue, InTech Open Access Publishers.","DOI":"10.5772\/59347"},{"key":"ref_10","unstructured":"Holt, D., de Castro Br\u00e1s, L., and Tulis, D. (2016). Cyclic nucleotide-driven protein kinase signaling in arterial smooth muscle (patho)physiology. Coronary Artery Disease\u2014Causes, Symptoms & Treatments, iCONCEPT Press, Ltd.. [1st ed.]."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1097\/MJT.0b013e318140052f","article-title":"Novel therapies for cyclic GMP control of vascular smooth muscle growth","volume":"15","author":"Tulis","year":"2008","journal-title":"Am. J. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.pharmthera.2017.01.001","article-title":"Adenylyl cyclase signalling complexes\u2014Pharmacological challenges and opportunities","volume":"172","author":"Halls","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Biel, M., and Michalakis, S. (2009). Cyclic nucleotide-gated channels. Handb. Exp. Pharmacol., 111\u2013136.","DOI":"10.1007\/978-3-540-68964-5_7"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.pbiomolbio.2016.01.001","article-title":"The popeye domain containing protein family\u2014A novel class of cAMP effectors with important functions in multiple tissues","volume":"120","author":"Schindler","year":"2016","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1385\/CBB:43:1:095","article-title":"The popeye domain-containing gene family","volume":"43","author":"Brand","year":"2005","journal-title":"Cell Biochem. Biophys."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.gene.2015.06.063","article-title":"Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: Structure, function and therapeutics","volume":"570","author":"Banerjee","year":"2015","journal-title":"Gene"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Adderley, S.P., Martin, D.N., and Tulis, D.A. (2015). Exchange protein activated by cAMP (Epac) controls migration of vascular smooth muscle cells in concentration- and time-dependent manner. Arch. Physiol., 2.","DOI":"10.7243\/2055-0898-2-2"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3217","DOI":"10.1242\/jcs.02416","article-title":"A-kinase-anchoring proteins","volume":"118","author":"Langeberg","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7887","DOI":"10.1074\/jbc.M114.622613","article-title":"Huntingtin-associated protein 1 (hap1) is a cGMP-dependent kinase anchoring protein (gkap) specific for the cGMP-dependent protein kinase ibeta isoform","volume":"290","author":"Corradini","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1016\/j.cellsig.2008.03.009","article-title":"cGMP-dependent protein kinase anchoring by IRAG regulates its nuclear translocation and transcriptional activity","volume":"20","author":"Casteel","year":"2008","journal-title":"Cell. Signal."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fphar.2012.00010","article-title":"Phosphodiesterases regulate BAY 41-2272-induced VASP phosphorylation in vascular smooth muscle cells","volume":"3","author":"Adderley","year":"2012","journal-title":"Front. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1126\/science.1075762","article-title":"The protein kinase complement of the human genome","volume":"298","author":"Manning","year":"2002","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nrm2203","article-title":"Mechanisms of specificity in protein phosphorylation","volume":"8","author":"Ubersax","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Khalil, R.A. (2010). Regulation of Vascular Smooth Muscle Function, Morgan & Claypool Life Sciences.","DOI":"10.4199\/C00012ED1V01Y201005ISP007"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1126\/science.1862342","article-title":"Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase","volume":"253","author":"Knighton","year":"1991","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1146\/annurev.ph.56.030194.001321","article-title":"Structure and function of cyclic nucleotide-dependent protein kinases","volume":"56","author":"Francis","year":"1994","journal-title":"Annu. Rev. Physiol."},{"key":"ref_27","first-page":"H237","article-title":"cGMP signals mainly through cAMP kinase in permeabilized murine aorta","volume":"292","author":"Worner","year":"2007","journal-title":"Am. J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Stone, J.D., Holt, A.W., Shaver, P.R., Vuncannon, J.R., and Tulis, D.A. (2016). AMP-activated protein kinase inhibits arterial smooth muscle cell proliferation in vasodilator-stimulated phosphoprotein-dependent manner. J. Non-Inv. Vasc. Investig., 1.","DOI":"10.24966\/NIVI-7400\/100002"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1097\/FJC.0b013e31819715c4","article-title":"Antigrowth properties of BAY 41-2272 in vascular smooth muscle cells","volume":"53","author":"Mendelev","year":"2009","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1124\/jpet.111.183400","article-title":"The soluble guanylate cyclase stimulator BAY 41-2272 inhibits vascular smooth muscle growth through the cAMP-dependent protein kinase and cGMP-dependent protein kinase pathways","volume":"339","author":"Joshi","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1016\/j.cellsig.2016.06.012","article-title":"Soluble guanylyl cyclase-activated cyclic GMP-dependent protein kinase inhibits arterial smooth muscle cell migration independent of VASP-serine 239 phosphorylation","volume":"28","author":"Holt","year":"2016","journal-title":"Cell. Signal."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.1016\/j.febslet.2010.07.059","article-title":"Cyclic cytidine 3\u2032,5\u2032-monophosphate (cCMP) signals via cGMP kinase i","volume":"584","author":"Desch","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1515\/hsz-2012-0282","article-title":"CCMP, cUMP, cTMP, cIMP and cXMP as possible second messengers: Development of a hypothesis based on studies with soluble guanylyl cyclase alpha(1)beta(1)","volume":"394","author":"Beste","year":"2013","journal-title":"Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1152\/physiol.00034.2011","article-title":"Novel Ser\/Thr protein phosphatases in cell death regulation","volume":"27","author":"Sun","year":"2012","journal-title":"Physiology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.cell.2009.10.006","article-title":"Serine\/threonine phosphatases: Mechanism through structure","volume":"139","author":"Shi","year":"2009","journal-title":"Cell"},{"key":"ref_36","first-page":"H369","article-title":"AMP-activated protein kinase inhibits vascular smooth muscle cell proliferation and migration and vascular remodeling following injury","volume":"304","author":"Stone","year":"2013","journal-title":"Am. J. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1016\/j.bmcl.2017.02.065","article-title":"Exchange proteins directly activated by cAMP (Epacs): Emerging therapeutic targets","volume":"27","author":"Wang","year":"2017","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/nrg2707","article-title":"Kinase mutations in human disease: Interpreting genotype-phenotype relationships","volume":"11","author":"Lahiry","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/S0140-6736(14)60606-1","article-title":"Protein kinases as cardiovascular therapeutic targets","volume":"384","author":"Kompa","year":"2014","journal-title":"Lancet"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"99","DOI":"10.2174\/1573408013666161128144216","article-title":"Protein kinases as drug targets in human and animal diseases","volume":"13","author":"Kini","year":"2017","journal-title":"Curr. Enzym. Inhib."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.3390\/ph3072111","article-title":"Protein kinases as drug development targets for heart disease therapy","volume":"3","author":"Dhalla","year":"2010","journal-title":"Pharmaceuticals"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nrd773","article-title":"Protein kinases\u2014The major drug targets of the twenty-first century?","volume":"1","author":"Cohen","year":"2002","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Wang, D., Wang, Z., Zhang, L., and Wang, Y. (2017). Roles of cells from the arterial vessel wall in atherosclerosis. Mediat. Inflamm., 2017.","DOI":"10.1155\/2017\/8135934"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3013","DOI":"10.1113\/JP270033","article-title":"Origin and differentiation of vascular smooth muscle cells","volume":"593","author":"Wang","year":"2015","journal-title":"J. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1161\/hc0902.104353","article-title":"Inflammation and atherosclerosis","volume":"105","author":"Libby","year":"2002","journal-title":"Circulation"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nrcardio.2009.55","article-title":"Obesity, inflammation, and atherosclerosis","volume":"6","author":"Rocha","year":"2009","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/S1471-4906(03)00117-0","article-title":"Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response","volume":"24","author":"Muller","year":"2003","journal-title":"Trends Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s00011-004-1282-0","article-title":"Anti-adhesion molecule strategies as potential neuroprotective agents in cerebral ischemia: A critical review of the literature","volume":"53","author":"Sughrue","year":"2004","journal-title":"Inflamm. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1038\/362801a0","article-title":"The pathogenesis of atherosclerosis: A perspective for the 1990s","volume":"362","author":"Ross","year":"1993","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Tian, D.Y., Jin, X.R., Zeng, X., and Wang, Y. (2017). Notch signaling in endothelial cells: Is it the therapeutic target for vascular neointimal hyperplasia?. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18081615"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1586\/erc.12.33","article-title":"Therapeutic strategies to combat neointimal hyperplasia in vascular grafts","volume":"10","author":"Collins","year":"2012","journal-title":"Expert Rev. Cardiovasc. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.hfc.2007.10.004","article-title":"The cardiac cycle and the physiologic basis of left ventricular contraction, ejection, relaxation, and filling","volume":"4","author":"Fukuta","year":"2008","journal-title":"Heart Fail. Clin."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.mbs.2008.04.001","article-title":"A condition for setting off ectopic waves in computational models of excitable cells","volume":"213","author":"Tveito","year":"2008","journal-title":"Math. Biosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"C1","DOI":"10.1152\/ajpcell.1983.245.1.C1","article-title":"Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum","volume":"245","author":"Fabiato","year":"1983","journal-title":"Am. J. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/0735-1097(88)90113-1","article-title":"Influence of altered inotropy and lusitropy on ventricular pressure-volume loops","volume":"11","author":"Katz","year":"1988","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1093\/cvr\/cvr069","article-title":"Establishment of the mouse ventricular conduction system","volume":"91","author":"Miquerol","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1161\/CIRCRESAHA.117.310230","article-title":"Calcium and excitation-contraction coupling in the heart","volume":"121","author":"Eisner","year":"2017","journal-title":"Circ. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev-physiol-012110-142145","article-title":"Heart valve structure and function in development and disease","volume":"73","author":"Hinton","year":"2011","journal-title":"Annu. Rev. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/978-3-319-57613-8_12","article-title":"The innate immune response in myocardial infarction, repair, and regeneration","volume":"1003","author":"Gentek","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1161\/CIR.0b013e3182009701","article-title":"Heart disease and stroke statistics\u20142011 update: A report from the American Heart Association","volume":"123","author":"Roger","year":"2011","journal-title":"Circulation"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.tcm.2017.03.002","article-title":"Type 2 myocardial infarction due to supply-demand mismatch","volume":"27","author":"Mihatov","year":"2017","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.mcna.2007.03.005","article-title":"Pathophysiology of acute myocardial infarction","volume":"91","author":"Burke","year":"2007","journal-title":"Med. Clin. N. Am."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1093\/eurheartj\/ehv592","article-title":"Pathophysiology of st-segment elevation myocardial infarction: Novel mechanisms and treatments","volume":"37","author":"Montecucco","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ijcard.2004.04.013","article-title":"Myocardial ischemia\/reperfusion-injury, a clinical view on a complex pathophysiological process","volume":"100","author":"Moens","year":"2005","journal-title":"Int. J. Cardiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1136\/heartjnl-2016-309530","article-title":"Assessment and classification of patients with myocardial injury and infarction in clinical practice","volume":"103","author":"Chapman","year":"2017","journal-title":"Heart"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1161\/CIR.0b013e31826e1058","article-title":"Third universal definition of myocardial infarction","volume":"126","author":"Thygesen","year":"2012","journal-title":"Circulation"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12947-017-0099-2","article-title":"The clinical use of stress echocardiography in ischemic heart disease","volume":"15","author":"Sicari","year":"2017","journal-title":"Cardiovasc. Ultrasound"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Kalogeris, T., Baines, C.P., Krenz, M., and Korthuis, R.J. (2016). Ischemia\/reperfusion. Compr. Physiol., 113\u2013170.","DOI":"10.1002\/cphy.c160006"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/B978-0-12-394309-5.00006-7","article-title":"Cell biology of ischemia\/reperfusion injury","volume":"298","author":"Kalogeris","year":"2012","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.yjmcc.2014.11.005","article-title":"The mitochondrial permeability transition pore and its role in myocardial ischemia reperfusion injury","volume":"78","author":"Ong","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.1074\/jbc.M006825200","article-title":"Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic nNAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart","volume":"276","author":"Menabo","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2478","DOI":"10.1111\/j.1582-4934.2010.01249.x","article-title":"Interplay between Ca2+ cycling and mitochondrial permeability transition pores promotes reperfusion-induced injury of cardiac myocytes","volume":"15","author":"Abdallah","year":"2011","journal-title":"J. Cell. Mol. Med."},{"key":"ref_73","first-page":"935","article-title":"Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: Trials and tribulations","volume":"38","author":"Hausenloy","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_74","first-page":"e25414","article-title":"Evaluation of the clinical and procedural predictive factors of no-reflow phenomenon following primary percutaneous coronary intervention","volume":"4","author":"Abdi","year":"2015","journal-title":"Res. Cardiovasc. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1152\/physrev.00014.2006","article-title":"Arrhythmogenic ion-channel remodeling in the heart: Heart failure, myocardial infarction, and atrial fibrillation","volume":"87","author":"Nattel","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1056\/NEJMra071667","article-title":"Myocardial reperfusion injury","volume":"357","author":"Yellon","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1161\/CIRCRESAHA.116.301312","article-title":"Inflammatory and immune responses in the arterial media","volume":"116","author":"Tellides","year":"2015","journal-title":"Circ. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ajpath.2017.09.007","article-title":"Platelet cd40 mediates leukocyte recruitment and neointima formation after arterial denudation injury in atherosclerosis-prone mice","volume":"188","author":"Jin","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.yjmcc.2011.07.029","article-title":"Nitric oxide synthase and cyclic GMP signaling in cardiac myocytes: From contractility to remodeling","volume":"52","author":"Hammond","year":"2012","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0031-6997(24)01457-1","article-title":"Guanylyl cyclases and signaling by cyclic GMP","volume":"52","author":"Lucas","year":"2000","journal-title":"Pharmacol. Rev."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1161\/01.RES.87.12.1095","article-title":"Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C","volume":"87","author":"Kamp","year":"2000","journal-title":"Circ. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.redox.2014.05.006","article-title":"Mitochondrial reactive oxygen species: A double edged sword in ischemia\/reperfusion vs. preconditioning","volume":"2","author":"Kalogeris","year":"2014","journal-title":"Redox Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"186","DOI":"10.4330\/wjc.v3.i6.186","article-title":"Ischemia\/reperfusion injury and cardioprotective mechanisms: Role of mitochondria and reactive oxygen species","volume":"3","author":"Perrelli","year":"2011","journal-title":"World J. Cardiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"863","DOI":"10.2217\/fca.12.58","article-title":"Mitochondrial membrane permeabilization and cell death during myocardial infarction: Roles of calcium and reactive oxygen species","volume":"8","author":"Webster","year":"2012","journal-title":"Future Cardiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.pharmthera.2011.05.010","article-title":"Management of the no-reflow phenomenon","volume":"132","author":"Butler","year":"2011","journal-title":"Pharmacol. Ther."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1161\/CIRCRESAHA.115.306569","article-title":"Moving forwards by blocking back-flow: The yin and yang of MI therapy","volume":"118","author":"Pell","year":"2016","journal-title":"Circ. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/1440-1681.12339","article-title":"Effect of inflammatory factor-induced cyclo-oxygenase expression on the development of reperfusion-related no-reflow phenomenon in acute myocardial infarction","volume":"42","author":"Jiao","year":"2015","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_88","first-page":"337","article-title":"Initial infarct size predicts subsequent cardiac remodeling in the rat infarct model: An in vivo serial pinhole gated spect study","volume":"47","author":"Maskali","year":"2006","journal-title":"J. Nuclear Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ahj.2017.02.028","article-title":"Relationship between therapeutic effects on infarct size in acute myocardial infarction and therapeutic effects on 1-year outcomes: A patient-level analysis of randomized clinical trials","volume":"188","author":"Selker","year":"2017","journal-title":"Am. Heart J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1097\/FJC.0000000000000003","article-title":"The immune system and the remodeling infarcted heart: Cell biological insights and therapeutic opportunities","volume":"63","author":"Frangogiannis","year":"2014","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Stefanon, I., Valero-Munoz, M., Fernandes, A.A., Ribeiro, R.F., Rodriguez, C., Miana, M., Martinez-Gonzalez, J., Spalenza, J.S., Lahera, V., and Vassallo, P.F. (2013). Left and right ventricle late remodeling following myocardial infarction in rats. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064986"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.yjmcc.2010.10.033","article-title":"Transforming growth factor (TGF)-beta signaling in cardiac remodeling","volume":"51","author":"Dobaczewski","year":"2011","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1161\/CIRCRESAHA.115.306656","article-title":"From c-reactive protein to interleukin-6 to interleukin-1: Moving upstream to identify novel targets for atheroprotection","volume":"118","author":"Ridker","year":"2016","journal-title":"Circ. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.cyto.2013.03.020","article-title":"Il-6 and its receptors in coronary artery disease and acute myocardial infarction","volume":"62","author":"Anderson","year":"2013","journal-title":"Cytokine"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/nrrheum.2017.142","article-title":"Giant cell arteritis and polymyalgia rheumatica: Current challenges and opportunities","volume":"13","author":"Dejaco","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1093\/cvr\/cvt115","article-title":"Biological responses in stented arteries","volume":"99","author":"Chaabane","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Didion, S.P. (2017). Cellular and oxidative mechanisms associated with interleukin-6 signaling in the vasculature. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122563"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.hfc.2009.04.001","article-title":"Inflammatory biomarkers in heart failure revisited: Much more than innocent bystanders","volume":"5","author":"Schefold","year":"2009","journal-title":"Heart Fail. Clin."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.cyto.2011.06.014","article-title":"Serum levels of interleukin (il)-27 in patients with ischemic heart disease","volume":"56","author":"Jafarzadeh","year":"2011","journal-title":"Cytokine"},{"key":"ref_100","first-page":"245","article-title":"Serial changes in plasma levels of cytokines in patients with coronary artery disease","volume":"1","author":"Heinisch","year":"2005","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1023\/A:1006846430224","article-title":"Pyrrolidine dithiocarbamate inhibits cytokine-induced vcam-1 gene expression in rat cardiac myocytes","volume":"177","author":"Hattori","year":"1997","journal-title":"Mol. Cell. Biochem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1160\/th14-04-0299","article-title":"TNF-induced endothelial barrier disruption: Beyond actin and rho","volume":"112","author":"Millan","year":"2014","journal-title":"Thromb. Haemost."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s11010-016-2922-8","article-title":"Interleukin-18-induced cell adhesion molecule expression is associated with feedback regulation by PPAR-gamma and Nf-kappa-b in apo e-\/- mice","volume":"428","author":"Bhat","year":"2017","journal-title":"Mol. Cell. Biochem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0008-6363(01)00434-5","article-title":"The inflammatory response in myocardial infarction","volume":"53","author":"Frangogiannis","year":"2002","journal-title":"Cardiovasc. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1073\/pnas.041611398","article-title":"Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta","volume":"98","author":"Pomerantz","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s11897-014-0231-7","article-title":"Targeting interleukin-1 in heart failure and inflammatory heart disease","volume":"12","author":"Raleigh","year":"2015","journal-title":"Curr. Heart Fail. Rep."},{"key":"ref_107","first-page":"H340","article-title":"New insights into the pathological role of TNF-alpha in early cardiac dysfunction and subsequent heart failure after infarction in rats","volume":"287","author":"Berthonneche","year":"2004","journal-title":"Am. J. Physiol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nrcardio.2015.169","article-title":"Regulatory t cells in cardiovascular diseases","volume":"13","author":"Meng","year":"2016","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1097\/CJI.0000000000000036","article-title":"High-dose interleukin 2-induced myocarditis: Can myocardial damage reversibility be assessed by cardiac MRI?","volume":"37","author":"Chow","year":"2014","journal-title":"J. Immunother."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e99","DOI":"10.1259\/bjr\/13448473","article-title":"Fulminant myocarditis owing to high-dose interleukin-2 therapy for metastatic melanoma","volume":"84","author":"Thavendiranathan","year":"2011","journal-title":"Br. J. Radiol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.cyto.2014.12.024","article-title":"The varying faces of IL-6: From cardiac protection to cardiac failure","volume":"74","author":"Fontes","year":"2015","journal-title":"Cytokine"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1536\/jhj.45.183","article-title":"Interleukin-6 and cardiovascular diseases","volume":"45","author":"Kanda","year":"2004","journal-title":"Jpn. Heart J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1042\/CS20110340","article-title":"IL-6\/IL-6 receptor system and its role in physiological and pathological conditions","volume":"122","author":"Mihara","year":"2012","journal-title":"Clin. Sci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1111\/imj.13483","article-title":"Giant cell arteritis: Beyond temporal artery biopsy and steroids","volume":"47","author":"Ninan","year":"2017","journal-title":"Intern. Med. J."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0735-1097(97)00494-4","article-title":"Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure","volume":"31","author":"Tsutamoto","year":"1998","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.ccr.2011.03.009","article-title":"Stat3\/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer","volume":"19","author":"Lesina","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1161\/ATVBAHA.111.229435","article-title":"Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice","volume":"32","author":"Schuett","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.yjmcc.2006.12.004","article-title":"Anti-rat soluble IL-6 receptor antibody down-regulates cardiac IL-6 and improves cardiac function following trauma-hemorrhage","volume":"42","author":"Yang","year":"2007","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1096\/fj.99-1003rev","article-title":"The soluble interleukin 6 receptor: Mechanisms of production and implications in disease","volume":"15","author":"Jones","year":"2001","journal-title":"FASEB J."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1093\/cvr\/cvq078","article-title":"Antibody against interleukin-6 receptor attenuates left ventricular remodelling after myocardial infarction in mice","volume":"87","author":"Kobara","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.7150\/ijbs.4989","article-title":"IL-6 trans-signaling via the soluble IL-6 receptor: Importance for the pro-inflammatory activities of IL-6","volume":"8","year":"2012","journal-title":"Int. J. Biol. Sci."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s10741-014-9431-1","article-title":"Role of interleukin-6 in regulation of immune responses to remodeling after myocardial infarction","volume":"20","author":"Huang","year":"2014","journal-title":"Heart Fail. Rev."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s10741-010-9170-x","article-title":"Stat3 and cardiac remodeling","volume":"16","author":"Haghikia","year":"2011","journal-title":"Heart Fail. Rev."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1161\/CIRCULATIONAHA.109.933127","article-title":"Continuous glycoprotein-130-mediated signal transducer and activator of transcription-3 activation promotes inflammation, left ventricular rupture, and adverse outcome in subacute myocardial infarction","volume":"122","author":"Shukla","year":"2010","journal-title":"Circulation"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1113\/jphysiol.2005.087478","article-title":"Both cgmp and peroxynitrite mediate chronic interleukin-6-induced negative inotropy in adult rat ventricular myocytes","volume":"566","author":"Yu","year":"2005","journal-title":"J. Physiol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.cellsig.2010.03.009","article-title":"A new regulation of IL-6 production in adult cardiomyocytes by beta-adrenergic and IL-1 beta receptors and induction of cellular hypertrophy by IL-6 trans-signalling","volume":"22","author":"Lefebvre","year":"2010","journal-title":"Cell. Signal."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/0014-5793(94)00459-5","article-title":"Cyclic gmp in the perfused rat heart. Effect of ischaemia, anoxia and nitric oxide synthase inhibitor","volume":"345","author":"Depre","year":"1994","journal-title":"FEBS Lett."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1007\/s00395-005-0543-6","article-title":"Post-conditioning reduces infarct size in the isolated rat heart: Role of coronary flow and pressure and the nitric oxide\/cgmp pathway","volume":"101","author":"Penna","year":"2006","journal-title":"Basic Res. Cardiol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1023\/A:1006800205787","article-title":"Role of cyclic nucleotide phosphodiesterases in ischemic preconditioning","volume":"186","author":"Lochner","year":"1998","journal-title":"Mol. Cell. Biochem."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1038\/sj.bjp.0707409","article-title":"Cyclic GMP and protein kinase-g in myocardial ischaemia-reperfusion: Opportunities and obstacles for survival signaling","volume":"152","author":"Burley","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/oxfordjournals.jbchem.a123339","article-title":"Regulation of the cardiac ryanodine receptor by protein kinase-dependent phosphorylation","volume":"109","author":"Takasago","year":"1991","journal-title":"J. Biochem."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.cardiores.2005.08.010","article-title":"Role of phospholamban phosphorylation on Thr17 in cardiac physiological and pathological conditions","volume":"68","author":"Mattiazzi","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1113\/jphysiol.2001.014126","article-title":"Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes","volume":"540","author":"Layland","year":"2002","journal-title":"J. Physiol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1111\/bph.12677","article-title":"Pathophysiology of isoprostanes in the cardiovascular system: Implications of isoprostane-mediated thromboxane a2 receptor activation","volume":"171","author":"Bauer","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Chigaev, A., Smagley, Y., and Sklar, L.A. (2011). Nitric oxide\/cGMP pathway signaling actively down-regulates alpha4beta1-integrin affinity: An unexpected mechanism for inducing cell de-adhesion. BMC Immunol., 12.","DOI":"10.1186\/1471-2172-12-28"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1161\/CIRCULATIONAHA.117.028723","article-title":"cGMP-elevating compounds and ischemic conditioning provide cardioprotection against ischemia and reperfusion injury via cardiomyocyte-specific BK channels","volume":"136","author":"Frankenreiter","year":"2017","journal-title":"Circulation"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.yjmcc.2017.01.015","article-title":"The effect of PKA-mediated phosphorylation of ryanodine receptor on SR Ca(2+) leak in ventricular myocytes","volume":"104","author":"Bovo","year":"2017","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1093\/cvr\/cvw026","article-title":"Selective phosphorylation of PKA targets after beta-adrenergic receptor stimulation impairs myofilament function in mybpc3-targeted hcm mouse model","volume":"110","author":"Najafi","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"I43","DOI":"10.1007\/s003950200028","article-title":"Functional interplay between dual site phospholambam phosphorylation: Insights from genetically altered mouse models","volume":"97","author":"Chu","year":"2002","journal-title":"Basic Res. Cardiol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1113\/jphysiol.2003.045260","article-title":"Protein kinase C and A sites on troponin I regulate myofilament Ca2+ sensitivity and ATPase activity in the mouse myocardium","volume":"552","author":"Pi","year":"2003","journal-title":"J. Physiol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"4707","DOI":"10.1113\/JP272333","article-title":"Beta-adrenergic augmentation of cardiac contractility is dependent on PKA-mediated phosphorylation of myosin-binding protein c and troponin i","volume":"594","author":"Callaghan","year":"2016","journal-title":"J. Physiol."},{"key":"ref_142","first-page":"582","article-title":"Phosphorylation of cardiac myosin-binding protein-c is a critical mediator of diastolic function","volume":"8","author":"Rosas","year":"2015","journal-title":"Circulation"},{"key":"ref_143","first-page":"H1605","article-title":"Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure","volume":"307","author":"Wilson","year":"2014","journal-title":"Am. J. Physiol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.yjmcc.2013.04.012","article-title":"Characterization of the cardiac myosin binding protein-c phosphoproteome in healthy and failing human hearts","volume":"60","author":"Kooij","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/nature01307","article-title":"The molecule pages database","volume":"420","author":"Li","year":"2002","journal-title":"Nature"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nature08144","article-title":"The structure and function of G-protein-coupled receptors","volume":"459","author":"Rosenbaum","year":"2009","journal-title":"Nature"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/nrd2199","article-title":"How many drug targets are there?","volume":"5","author":"Overington","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nrd.2016.230","article-title":"A comprehensive map of molecular drug targets","volume":"16","author":"Santos","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.pharmthera.2004.08.008","article-title":"Mutant G-protein-coupled receptors as a cause of human diseases","volume":"104","author":"Schoneberg","year":"2004","journal-title":"Pharmacol. Ther."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1016\/j.bbamem.2006.09.029","article-title":"Impact of GPCRs in clinical medicine: Monogenic diseases, genetic variants and drug targets","volume":"1768","author":"Insel","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_151","first-page":"2","article-title":"G protein-coupled receptors as disease targets: Emerging paradigms","volume":"10","author":"Cook","year":"2010","journal-title":"Ochsner J."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"354","DOI":"10.3389\/fphys.2013.00354","article-title":"Acidic tumor microenvironment and pH-sensing G protein-coupled receptors","volume":"4","author":"Justus","year":"2013","journal-title":"Front. Physiol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nature01905","article-title":"Proton-sensing G-protein-coupled receptors","volume":"425","author":"Ludwig","year":"2003","journal-title":"Nature"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"9083","DOI":"10.1074\/jbc.M407832200","article-title":"Identification of T cell death-associated gene 8 (TDAG8) as a novel acid sensing G-protein-coupled receptor","volume":"280","author":"Ishii","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1016\/j.cellsig.2005.06.002","article-title":"Proton-sensing and lysolipid-sensitive G-protein-coupled receptors: A novel type of multi-functional receptors","volume":"17","author":"Tomura","year":"2005","journal-title":"Cell. Signal."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1016\/j.cellsig.2013.07.022","article-title":"Regulation of inflammation by extracellular acidification and proton-sensing GPCRs","volume":"25","author":"Okajima","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_157","first-page":"99","article-title":"Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress","volume":"2015","author":"Sanderlin","year":"2015","journal-title":"Cell Health Cytoskelet."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1128\/MCB.01909-06","article-title":"Vascular abnormalities in mice deficient for the G protein-coupled receptor GPR4 that functions as a pH sensor","volume":"27","author":"Yang","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Chen, A., Dong, L., Leffler, N.R., Asch, A.S., Witte, O.N., and Yang, L.V. (2011). Activation of GPR4 by acidosis increases endothelial cell adhesion through the cAMP\/Epac pathway. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027586"},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Dong, L., Li, Z., Leffler, N.R., Asch, A.S., Chi, J.T., and Yang, L.V. (2013). Acidosis activation of the proton-sensing GPR4 receptor stimulates vascular endothelial cell inflammatory responses revealed by transcriptome analysis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061991"},{"key":"ref_161","first-page":"H731","article-title":"Ovarian cancer G protein-coupled receptor 1-dependent and -independent vascular actions to acidic pH in human aortic smooth muscle cells","volume":"299","author":"Liu","year":"2010","journal-title":"Am. J. Physiol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1093\/bioinformatics\/btl483","article-title":"Gather: A systems approach to interpreting genomic signatures","volume":"22","author":"Chang","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"34458","DOI":"10.1074\/jbc.M505287200","article-title":"Prostaglandin i(2) production and cAMP accumulation in response to acidic extracellular pH through OGR1 in human aortic smooth muscle cells","volume":"280","author":"Tomura","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1002\/jcb.21930","article-title":"The p38 mitogen-activated protein kinase pathway is involved in the regulation of heme oxygenase-1 by acidic extracellular pH in aortic smooth muscle cells","volume":"105","author":"Guan","year":"2008","journal-title":"J. Cell. Biochem."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"L867","DOI":"10.1152\/ajplung.00455.2004","article-title":"Chronic hypoxia elevates intracellular pH and activates Na+\/H+ exchange in pulmonary arterial smooth muscle cells","volume":"289","author":"Rios","year":"2005","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1021\/cb300001m","article-title":"Regulated expression of pH sensing G protein-coupled receptor-68 identified through chemical biology defines a new drug target for ischemic heart disease","volume":"7","author":"Russell","year":"2012","journal-title":"ACS Chem. Biol."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1021\/acsmedchemlett.6b00014","article-title":"Identification of a potent and selective GPR4 antagonist as a drug lead for the treatment of myocardial infarction","volume":"7","author":"Fukuda","year":"2016","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1161\/01.ATV.0000251995.73307.2d","article-title":"The roles of proteinase-activated receptors in the vascular physiology and pathophysiology","volume":"27","author":"Hirano","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1161\/CIRCULATIONAHA.105.574830","article-title":"Protease-activated receptors in cardiovascular diseases","volume":"114","author":"Leger","year":"2006","journal-title":"Circulation"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/35025229","article-title":"Thrombin signalling and protease-activated receptors","volume":"407","author":"Coughlin","year":"2000","journal-title":"Nature"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.pharmthera.2012.01.007","article-title":"Physiology, pharmacology, and therapeutic potential of protease-activated receptors in vascular disease","volume":"134","author":"Lee","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1016\/j.bbadis.2014.06.004","article-title":"Soluble dpp4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2","volume":"1842","author":"Wronkowitz","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S0031-6997(24)01493-5","article-title":"Proteinase-activated receptors","volume":"53","author":"Macfarlane","year":"2001","journal-title":"Pharmacol. Rev."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1124\/mol.104.003103","article-title":"The cardiovascular actions of protease-activated receptors","volume":"67","author":"Steinberg","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.vph.2014.06.001","article-title":"Functional role of protease activated receptors in vascular biology","volume":"62","author":"Alberelli","year":"2014","journal-title":"Vasc. Pharmacol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"61","DOI":"10.2174\/1568016033356715","article-title":"Proteinase-activated receptor-2: Physiological and pathophysiological roles","volume":"1","author":"Coelho","year":"2003","journal-title":"Curr. Med. Chem. Cardiovasc. Hematol. Agents"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s40268-016-0158-4","article-title":"Vorapaxar: The current role and future directions of a novel protease-activated receptor antagonist for risk reduction in atherosclerotic disease","volume":"17","author":"Gryka","year":"2017","journal-title":"Drugs R D"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1161\/01.RES.75.6.1029","article-title":"Characterization of thrombin receptor expression during vascular lesion formation","volume":"75","author":"Wilcox","year":"1994","journal-title":"Circ. Res."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1097\/00005344-199711000-00016","article-title":"Expression of thrombin receptors in human atherosclerotic coronary arteries leads to an exaggerated vasoconstrictory response in vitro","volume":"30","author":"Ku","year":"1997","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"647","DOI":"10.3389\/fphar.2017.00647","article-title":"Protease-activated receptor-2 deficiency attenuates atherosclerotic lesion progression and instability in apolipoprotein e-deficient mice","volume":"8","author":"Zuo","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0092-8674(03)00432-X","article-title":"Mechanisms of TGF-beta signaling from cell membrane to the nucleus","volume":"113","author":"Shi","year":"2003","journal-title":"Cell"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/0962-8924(94)90202-X","article-title":"The TGF-beta family and its composite receptors","volume":"4","author":"Massague","year":"1994","journal-title":"Trends Cell Biol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1101\/gad.8.2.133","article-title":"The TGF-beta superfamily: New members, new receptors, and new genetic tests of function in different organisms","volume":"8","author":"Kingsley","year":"1994","journal-title":"Genes Dev."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/370341a0","article-title":"Mechanism of activation of the TGF-beta receptor","volume":"370","author":"Wrana","year":"1994","journal-title":"Nature"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1242\/jcs.00229","article-title":"Making sense of latent TGFbeta activation","volume":"116","author":"Annes","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/S1357-2725(03)00255-3","article-title":"Mammalian transforming growth factor-betas: Smad signaling and physio-pathological roles","volume":"36","author":"Javelaud","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_187","doi-asserted-by":"crossref","unstructured":"Gonzalez, D., Contreras, O., Rebolledo, D.L., Espinoza, J.P., van Zundert, B., and Brandan, E. (2017). Als skeletal muscle shows enhanced TGF-beta signaling, fibrosis and induction of fibro\/adipogenic progenitor markers. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0177649"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.2337\/db15-1122","article-title":"AMPK activation by metformin suppresses abnormal extracellular matrix remodeling in adipose tissue and ameliorates insulin resistance in obesity","volume":"65","author":"Luo","year":"2016","journal-title":"Diabetes"},{"key":"ref_189","doi-asserted-by":"crossref","unstructured":"Rodriguez-Vita, J., Sanchez-Galan, E., Santamaria, B., Sanchez-Lopez, E., Rodrigues-Diez, R., Blanco-Colio, L.M., Egido, J., Ortiz, A., and Ruiz-Ortega, M. (2008). Essential role of TGF-beta\/Smad pathway on statin dependent vascular smooth muscle cell regulation. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003959"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1161\/01.CIR.0000165133.84978.E2","article-title":"Angiotensin ii activates the smad pathway in vascular smooth muscle cells by a transforming growth factor-beta-independent mechanism","volume":"111","author":"Esteban","year":"2005","journal-title":"Circulation"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1159\/000142612","article-title":"Density-dependent shift of transforming growth factor-beta-1 from inhibition to stimulation of vascular smooth muscle cell growth is based on unconventional regulation of proliferation, apoptosis and contact inhibition","volume":"46","author":"Hneino","year":"2009","journal-title":"J. Vasc. Res."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/2211-5463.12202","article-title":"Inhibition of the TGFbeta signalling pathway by cGMP and cGMP-dependent kinase i in renal fibrosis","volume":"7","author":"Schinner","year":"2017","journal-title":"FEBS Open Bio"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1210\/me.2011-1009","article-title":"cGMP inhibits TGF-beta signaling by sequestering Smad3 with cytosolic beta2-tubulin in pulmonary artery smooth muscle cells","volume":"25","author":"Gong","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s11684-014-0378-3","article-title":"Chronic inhibition of cyclic guanosine monophosphate-specific phosphodiesterase 5 prevented cardiac fibrosis through inhibition of transforming growth factor beta-induced smad signaling","volume":"8","author":"Gong","year":"2014","journal-title":"Front. Med."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1038\/onc.2008.20","article-title":"Structure\/function relationships underlying regulation of foxo transcription factors","volume":"27","author":"Obsil","year":"2008","journal-title":"Oncogene"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/dbio.2002.0780","article-title":"Forkhead transcription factors: Key players in development and metabolism","volume":"250","author":"Carlsson","year":"2002","journal-title":"Dev. Biol."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S0168-9525(03)00111-2","article-title":"Fox\u2019s in development and disease","volume":"19","author":"Lehmann","year":"2003","journal-title":"Trends Genet."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"7410","DOI":"10.1038\/sj.onc.1209086","article-title":"Foxo transcription factors at the interface between longevity and tumor suppression","volume":"24","author":"Greer","year":"2005","journal-title":"Oncogene"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/nrm2190","article-title":"Stressing the role of FOXO proteins in lifespan and disease","volume":"8","author":"Burgering","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/S1097-2765(04)00211-4","article-title":"The IGF-1\/pPI3K\/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors","volume":"14","author":"Stitt","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S0092-8674(00)80595-4","article-title":"Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor","volume":"96","author":"Brunet","year":"1999","journal-title":"Cell"},{"key":"ref_202","doi-asserted-by":"crossref","unstructured":"Loebel, M., Holzhauser, L., Hartwig, J.A., Shukla, P.C., Savvatis, K., Jenke, A., Gast, M., Escher, F., Becker, S.C., and Bauer, S. (2017). The forkhead transcription factor FOXO3 negatively regulates natural killer cell function and viral clearance in myocarditis. Eur. Heart J.","DOI":"10.1093\/eurheartj\/ehx624"},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.freeradbiomed.2017.01.037","article-title":"Foxo3a inhibits mitochondrial fission and protects against doxorubicin-induced cardiotoxicity by suppressing mief2","volume":"104","author":"Zhou","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jss.2014.05.005","article-title":"Metformin mitigates apoptosis in ischemic myocardium","volume":"192","author":"Elmadhun","year":"2014","journal-title":"J. Surg. Res."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1161\/01.ATV.0000156288.70849.26","article-title":"Activated forkhead transcription factor inhibits neointimal hyperplasia after angioplasty through induction of p27","volume":"25","author":"Park","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/mus.20897","article-title":"Foxo3a preferentially induces p27kip1 expression while impairing muscle precursor cell-cycle progression","volume":"37","author":"Rathbone","year":"2008","journal-title":"Muscle Nerve"},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1161\/01.RES.0000257945.97958.77","article-title":"Forkhead transcription factor Foxo3a is a negative regulator of angiogenic immediate early gene cyr61, leading to inhibition of vascular smooth muscle cell proliferation and neointimal hyperplasia","volume":"100","author":"Lee","year":"2007","journal-title":"Circ. Res."},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"C278","DOI":"10.1152\/ajpcell.00391.2013","article-title":"Smad3 augments FoxO3-induced MuRF-1 promoter activity in a DNA-binding-dependent manner","volume":"307","author":"Bollinger","year":"2014","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0092-8674(04)00298-3","article-title":"Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation","volume":"117","author":"Seoane","year":"2004","journal-title":"Cell"},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.ccr.2006.07.019","article-title":"C\/EBPbeta at the core of the TGFbeta cytostatic response and its evasion in metastatic breast cancer cells","volume":"10","author":"Gomis","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1128\/MCB.00175-10","article-title":"Inactivation of FoxO3a and subsequent downregulation of PGC-1 alpha mediate nitric oxide-induced endothelial cell migration","volume":"30","author":"Borniquel","year":"2010","journal-title":"Mol. Cell. Biol."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"5726","DOI":"10.1128\/MCB.23.16.5726-5737.2003","article-title":"Activation of the phosphatidylinositol 3-kinase\/protein kinase Akt pathway mediates nitric oxide-induced endothelial cell migration and angiogenesis","volume":"23","author":"Kawasaki","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/S0005-2728(99)00024-9","article-title":"Guanylate cyclase and the NO\/cGMP signaling pathway","volume":"1411","author":"Denninger","year":"1999","journal-title":"Biochim. Biophys. Acta"}],"container-title":["Journal of Cardiovascular Development and Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2308-3425\/5\/1\/6\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:52:14Z","timestamp":1760194334000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2308-3425\/5\/1\/6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,23]]},"references-count":213,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,3]]}},"alternative-id":["jcdd5010006"],"URL":"https:\/\/doi.org\/10.3390\/jcdd5010006","relation":{},"ISSN":["2308-3425"],"issn-type":[{"value":"2308-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,23]]}}}