{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T10:52:06Z","timestamp":1786791126289,"version":"build-2736575974"},"reference-count":195,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,19]],"date-time":"2021-06-19T00:00:00Z","timestamp":1624060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rutgers University","award":["Start Up Funds"],"award-info":[{"award-number":["Start Up Funds"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["4R00AG055701-03"],"award-info":[{"award-number":["4R00AG055701-03"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)\u2014particularly \u03b2ARs\u2014play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone\/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.<\/jats:p>","DOI":"10.3390\/cells10061552","type":"journal-article","created":{"date-parts":[[2021,6,20]],"date-time":"2021-06-20T22:00:02Z","timestamp":1624226402000},"page":"1552","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9768-4706","authenticated-orcid":false,"given":"Mariona","family":"Guitart-Mampel","sequence":"first","affiliation":[{"name":"Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Urquiza","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordana I.","family":"Borges","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9817-6319","authenticated-orcid":false,"given":"Anastasios","family":"Lymperopoulos","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8105-1701","authenticated-orcid":false,"given":"Maria E.","family":"Solesio","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Arts and Sciences, Rutgers University, Camden, NJ 08103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.15420\/cfr.2016:25:2","article-title":"Global Public Health Burden of Heart Failure","volume":"3","author":"Savarese","year":"2017","journal-title":"Card. Fail. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1161\/CIRCRESAHA.113.300308","article-title":"Adrenergic nervous system in heart failure: Pathophysiology and therapy","volume":"113","author":"Lymperopoulos","year":"2013","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Parker, B.M., Wertz, S.L., Pollard, C.M., Desimine, V.L., Maning, J., McCrink, K.A., and Lymperopoulos, A. (2018). Novel Insights into the Crosstalk between Mineralocorticoid Receptor and G Protein-Coupled Receptors in Heart Adverse Remodeling and Disease. Int. J. Mol. Sci., 19.","DOI":"10.20944\/preprints201811.0389.v1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1093\/eurheartj\/ehs041","article-title":"The human sympathetic nervous system: Its relevance in hypertension and heart failure","volume":"33","author":"Parati","year":"2012","journal-title":"Eur. Heart J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s10741-019-09901-2","article-title":"Sympathetic activation in congestive heart failure: An updated overview","volume":"26","author":"Grassi","year":"2021","journal-title":"Heart Fail. Rev."},{"key":"ref_6","first-page":"I59","article-title":"Abnormalities of peripheral sympathetic nervous system control in congestive heart failure","volume":"82","author":"Cohn","year":"1990","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1476-5381.2012.01994.x","article-title":"3-Nitropropionic acid induces autophagy by forming mitochondrial permeability transition pores rather than activating the mitochondrial fission pathway","volume":"168","author":"Solesio","year":"2013","journal-title":"Br. J. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/toxsci\/kfs218","article-title":"Characterization of mitophagy in the 6-hydoxydopamine Parkinson\u2019s disease model","volume":"129","author":"Solesio","year":"2012","journal-title":"Toxicol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.bbadis.2012.07.009","article-title":"The mitochondria-targeted anti-oxidant MitoQ reduces aspects of mitochondrial fission in the 6-OHDA cell model of Parkinson\u2019s disease","volume":"1832","author":"Solesio","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e12787","DOI":"10.1111\/acel.12787","article-title":"Carbonic anhydrase inhibition selectively prevents amyloid \u03b2 neurovascular mitochondrial toxicity","volume":"17","author":"Solesio","year":"2018","journal-title":"Aging Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/jbmr.3573","article-title":"Mitochondrial Function Is Compromised in Cortical Bone Osteocytes of Long-Lived Growth Hormone Receptor Null Mice","volume":"34","author":"Liu","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_12","first-page":"131058","article-title":"Mitochondrial dynamics and mitophagy in the 6-hydroxydopamine preclinical model of Parkinson\u2019s disease","volume":"2012","author":"Galindo","year":"2012","journal-title":"Parkinsons Dis."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Borden, E.A., Furey, M., Gattone, N.J., Hambardikar, V.D., Liang, X.H., Scoma, E.R., Abou Samra, A., LR, D.G., Dennis, D.J., and Fricker, D. (2020). Is there a link between inorganic polyphosphate (polyP), mitochondria, and neurodegeneration?. Pharm. Res., 105211.","DOI":"10.1016\/j.phrs.2020.105211"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1007\/s13105-013-0271-6","article-title":"The senescence-accelerated mouse prone-8 (SAM-P8) oxidative stress is associated with upregulation of renal NADPH oxidase system","volume":"69","author":"Baltanas","year":"2013","journal-title":"J. Physiol. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e00497","DOI":"10.1002\/prp2.497","article-title":"Adrenal \u03b2arrestin1 targeting for tobacco-associated cardiac dysfunction treatment: Aldosterone production as the mechanistic link","volume":"7","author":"Solesio","year":"2019","journal-title":"Pharm. Res. Perspect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1681\/ASN.2005040390","article-title":"Aldosterone stimulates reactive oxygen species production through activation of NADPH oxidase in rat mesangial cells","volume":"16","author":"Miyata","year":"2005","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1291\/hypres.31.363","article-title":"Aldosterone nongenomically produces NADPH oxidase-dependent reactive oxygen species and induces myocyte apoptosis","volume":"31","author":"Hayashi","year":"2008","journal-title":"Hypertens Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1097\/01.fjc.0000432861.55968.a6","article-title":"Heart failure and mitochondrial dysfunction: The role of mitochondrial fission\/fusion abnormalities and new therapeutic strategies","volume":"63","author":"Knowlton","year":"2014","journal-title":"J. Cardiovasc. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.1253\/circj.CJ-13-0557","article-title":"Cardiac dysfunction in mitochondrial disease. Clinical and molecular features","volume":"77","author":"Villar","year":"2013","journal-title":"Circ. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1006\/jmcc.2001.1378","article-title":"Mitochondrial dysfunction in cardiac disease: Ischemia--reperfusion, aging, and heart failure","volume":"33","author":"Lesnefsky","year":"2001","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6801","DOI":"10.1038\/s41598-018-25068-6","article-title":"Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A-Kinase Anchor Protein 12","volume":"8","author":"Ibarrola","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1080\/07853890.2017.1417631","article-title":"The role of mitochondrial dysfunction in cardiovascular disease: A brief review","volume":"50","author":"Chistiakov","year":"2018","journal-title":"Ann. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s10741-012-9340-0","article-title":"Mitochondrial dysfunction in heart failure","volume":"18","author":"Rosca","year":"2013","journal-title":"Heart Fail. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.yjmcc.2020.04.015","article-title":"The role of Drp1 in mitophagy and cell death in the heart","volume":"142","author":"Tong","year":"2020","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"H2181","DOI":"10.1152\/ajpheart.00554.2011","article-title":"Oxidative stress and heart failure","volume":"301","author":"Tsutsui","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.bbrc.2016.01.089","article-title":"Carvedilol promotes mitochondrial biogenesis by regulating the PGC-1\/TFAM pathway in human umbilical vein endothelial cells (HUVECs)","volume":"470","author":"Yao","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1126\/science.283.5407.1488","article-title":"Oxidative phosphorylation at the fin de siecle","volume":"283","author":"Saraste","year":"1999","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"R453","DOI":"10.1016\/j.cub.2014.03.034","article-title":"ROS function in redox signaling and oxidative stress","volume":"24","author":"Schieber","year":"2014","journal-title":"Curr. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1042\/BST20150206","article-title":"Inorganic polyphosphate (polyP) as an activator and structural component of the mitochondrial permeability transition pore","volume":"44","author":"Solesio","year":"2016","journal-title":"Biochem. Soc. Trans."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"102127","DOI":"10.1016\/j.ceca.2019.102127","article-title":"Inorganic polyphosphate is required for sustained free mitochondrial calcium elevation, following calcium uptake","volume":"86","author":"Solesio","year":"2020","journal-title":"Cell Calcium"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1042\/BCJ20200975","article-title":"Depletion of mitochondrial inorganic polyphosphate (polyP) in mammalian cells causes metabolic shift from oxidative phosphorylation to glycolysis","volume":"478","author":"Solesio","year":"2021","journal-title":"Biochem. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.abb.2018.12.019","article-title":"Dual role of inorganic polyphosphate in cardiac myocytes: The importance of polyP chain length for energy metabolism and mPTP activation","volume":"662","author":"Seidlmayer","year":"2019","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1085\/jgp.201210788","article-title":"Inorganic polyphosphate is a potent activator of the mitochondrial permeability transition pore in cardiac myocytes","volume":"139","author":"Seidlmayer","year":"2012","journal-title":"J. Gen. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"463","DOI":"10.4161\/chan.21939","article-title":"Inorganic polyphosphate--an unusual suspect of the mitochondrial permeability transition mystery","volume":"6","author":"Seidlmayer","year":"2012","journal-title":"Channels"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"9602","DOI":"10.1002\/jcb.27068","article-title":"A high-fat diet impairs mitochondrial biogenesis, mitochondrial dynamics, and the respiratory chain complex in rat myocardial tissues","volume":"119","author":"Chen","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.cardfail.2012.06.418","article-title":"Proteomic profiling implies mitochondrial dysfunction in tachycardia-induced heart failure","volume":"18","author":"Birner","year":"2012","journal-title":"J. Card. Fail."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"H529","DOI":"10.1152\/ajpheart.00267.2010","article-title":"Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes","volume":"299","author":"Dabkowski","year":"2010","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/ejhf.640","article-title":"Myocardial iron content and mitochondrial function in human heart failure: A direct tissue analysis","volume":"19","author":"Melenovsky","year":"2017","journal-title":"Eur. J. Heart Fail."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1161\/CIRCULATIONAHA.120.050498","article-title":"Myocardial Gene Expression Signatures in Human Heart Failure With Preserved Ejection Fraction","volume":"143","author":"Hahn","year":"2021","journal-title":"Circulation"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Sheeran, F.L., and Pepe, S. (2017). Mitochondrial bioenergetics and dysfunction in failing heart. Mitochondrial Dyn. Cardiovasc. Med., 65\u201380.","DOI":"10.1007\/978-3-319-55330-6_4"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.freeradbiomed.2018.09.019","article-title":"Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities","volume":"129","author":"Kiyuna","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.freeradbiomed.2018.01.012","article-title":"MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload","volume":"117","author":"Dabkowski","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1002\/cphy.c130037","article-title":"Regulation of aldosterone synthesis and secretion","volume":"4","author":"Bollag","year":"2014","journal-title":"Compr. Physiol."},{"key":"ref_44","first-page":"965","article-title":"The multifaceted mineralocorticoid receptor","volume":"4","year":"2014","journal-title":"Compr. Physiol."},{"key":"ref_45","unstructured":"Alhayek, S., and Preuss, C.V. (2021, May 03). Beta 1 Receptors, StatPearls, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/30422499\/."},{"key":"ref_46","first-page":"126","article-title":"Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS)","volume":"4","author":"Caldiz","year":"2013","journal-title":"Front. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Daubert, M.A., Yow, E., Dunn, G., Marchev, S., Barnhart, H., Douglas, P.S., O\u2019Connor, C., Goldstein, S., Udelson, J.E., and Sabbah, H.N. (2017). Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide. Circ. Heart Fail., 10.","DOI":"10.1161\/CIRCHEARTFAILURE.117.004389"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1016\/j.yjmcc.2011.08.025","article-title":"Pharmacological inhibition of \u03b2IIPKC is cardioprotective in late-stage hypertrophy","volume":"51","author":"Ferreira","year":"2011","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Ferreira, J.C., Boer, B.N., Grinberg, M., Brum, P.C., and Mochly-Rosen, D. (2012). Protein quality control disruption by PKC\u03b2II in heart failure; rescue by the selective PKC\u03b2II inhibitor, \u03b2IIV5-3. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033175"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1253\/circj.CJ-11-1360","article-title":"Identification of epsilonPKC targets during cardiac ischemic injury","volume":"76","author":"Budas","year":"2012","journal-title":"Circ. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1093\/cvr\/cvp334","article-title":"Ischaemic preconditioning improves proteasomal activity and increases the degradation of deltaPKC during reperfusion","volume":"85","author":"Churchill","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/s41569-018-0059-z","article-title":"Mitochondrial quality control mechanisms as molecular targets in cardiac ageing","volume":"15","author":"Picca","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1038\/nrm3013","article-title":"Mitochondrial fusion and fission in cell life and death","volume":"11","author":"Westermann","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"950.e1","DOI":"10.1016\/j.cell.2011.10.036","article-title":"SnapShot: Mitochondrial quality control","volume":"147","author":"Green","year":"2011","journal-title":"Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrm3028","article-title":"Mechanisms of mitophagy","volume":"12","author":"Youle","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1161\/CIRCULATIONAHA.115.020502","article-title":"Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure","volume":"133","author":"Shirakabe","year":"2016","journal-title":"Circulation"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"aad0116","DOI":"10.1126\/science.aad0116","article-title":"Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice","volume":"350","author":"Wai","year":"2015","journal-title":"Science"},{"key":"ref_58","unstructured":"Fountain, J.H., and Lappin, S.L. (2021, May 03). Physiology, Renin Angiotensin System, StatPearls, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/29261862\/."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"E1790","DOI":"10.1152\/ajpendo.00708.2006","article-title":"Aldosterone-induced EGFR expression: Interaction between the human mineralocorticoid receptor and the human EGFR promoter","volume":"292","author":"Grossmann","year":"2007","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1146\/annurev-pharmtox-070115-095427","article-title":"Epidermal Growth Factor Receptor Transactivation: Mechanisms, Pathophysiology, and Potential Therapies in the Cardiovascular System","volume":"56","author":"Forrester","year":"2016","journal-title":"Annu. Rev. Pharm. Toxicol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"161","DOI":"10.3389\/fendo.2013.00161","article-title":"The role of tissue Renin-Angiotensin-aldosterone system in the development of endothelial dysfunction and arterial stiffness","volume":"4","author":"Aroor","year":"2013","journal-title":"Front. Endocrinol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/nrneph.2013.110","article-title":"Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis","volume":"9","author":"Brown","year":"2013","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Tang, Y., Long, J., and Liu, J. (2014). Hyperglycemia-Associated Oxidative Stress Induces Autophagy: Involvement of the ROS-ERK\/JNK-p53 Pathway. Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging, Elsevier.","DOI":"10.1016\/B978-0-12-405530-8.00008-X"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1161\/HYPERTENSIONAHA.118.11873","article-title":"MR (Mineralocorticoid Receptor) Induces Adipose Tissue Senescence and Mitochondrial Dysfunction Leading to Vascular Dysfunction in Obesity","volume":"73","author":"Lefranc","year":"2019","journal-title":"Hypertension"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1042\/BST20190228","article-title":"The role of A-kinase anchoring proteins in cardiac oxidative stress","volume":"47","author":"Diviani","year":"2019","journal-title":"Biochem. Soc. Trans."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1093\/cvr\/cvq155","article-title":"AKAP121 downregulation impairs protective cAMP signals, promotes mitochondrial dysfunction, and increases oxidative stress","volume":"88","author":"Perrino","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1016\/j.bbadis.2014.05.036","article-title":"Aldosterone signaling and soluble adenylyl cyclase-a nexus for the kidney and vascular endothelium","volume":"1842","author":"Schmitz","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1007\/s00424-018-2157-5","article-title":"Mitochondrial cAMP and Ca2+ metabolism in adrenocortical cells","volume":"470","author":"Spat","year":"2018","journal-title":"Pfl\u00fcgers Arch."},{"key":"ref_69","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_70","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1083\/jcb.200211012","article-title":"PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: Defective regulation in heart failure","volume":"160","author":"Reiken","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.celrep.2015.06.017","article-title":"The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition","volume":"12","author":"Luongo","year":"2015","journal-title":"Cell Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/0306-3623(80)90040-3","article-title":"The effects of \u03b2-adrenergic receptor blockers on heart mitochondrial metabolism","volume":"11","author":"Bhayana","year":"1980","journal-title":"Gen. Pharm."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S1071-9164(98)90252-4","article-title":"Beta-receptor blockade decreases carnitine palmitoyl transferase I activity in dogs with heart failure","volume":"4","author":"Panchal","year":"1998","journal-title":"J. Card. Fail."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1111\/acel.12205","article-title":"Lifelong treatment with atenolol decreases membrane fatty acid unsaturation and oxidative stress in heart and skeletal muscle mitochondria and improves immunity and behavior, without changing mice longevity","volume":"13","author":"Gomez","year":"2014","journal-title":"Aging Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1016\/S0735-1097(02)01840-5","article-title":"Impact of beta-blocker treatment on the prognostic value of currently used risk predictors in congestive heart failure","volume":"39","author":"Zugck","year":"2002","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1161\/01.CIR.0000164270.72123.18","article-title":"Peak oxygen consumption as a predictor of death in patients with heart failure receiving \u03b2-blockers","volume":"111","author":"Young","year":"2005","journal-title":"Circulation"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/(SICI)1097-0185(199702)247:2<289::AID-AR15>3.0.CO;2-L","article-title":"Gross and microscopic anatomy of the human intrinsic cardiac nervous system","volume":"247","author":"Armour","year":"1997","journal-title":"Anat. Rec."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.molmed.2007.10.005","article-title":"Adrenal adrenoceptors in heart failure: Fine-tuning cardiac stimulation","volume":"13","author":"Lymperopoulos","year":"2007","journal-title":"Trends Mol. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ejphar.2015.05.019","article-title":"GPCR signaling and cardiac function","volume":"763","author":"Capote","year":"2015","journal-title":"Eur J. Pharm."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/bs.pmbts.2018.07.003","article-title":"Arrestins in the Cardiovascular System: An Update","volume":"159","author":"Lymperopoulos","year":"2018","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1093\/eurheartj\/17.suppl_B.8","article-title":"Cardiac adrenergic receptor effects of carvedilol","volume":"17","author":"Yoshikawa","year":"1996","journal-title":"Eur. Heart J."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.yjmcc.2013.01.002","article-title":"Calcium movements inside the sarcoplasmic reticulum of cardiac myocytes","volume":"58","author":"Bers","year":"2013","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/36362","article-title":"Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A","volume":"390","author":"Daaka","year":"1997","journal-title":"Nature"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1161\/01.CIR.100.22.2210","article-title":"Opposing effects of \u03b21- and \u03b22-adrenergic receptors on cardiac myocyte apoptosis: Role of a pertussis toxin-sensitive G protein","volume":"100","author":"Communal","year":"1999","journal-title":"Circulation"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1161\/01.RES.87.12.1172","article-title":"The \u03b22-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through Gi-dependent coupling to phosphatidylinositol 3\u2032-kinase","volume":"87","author":"Chesley","year":"2000","journal-title":"Circ. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1111\/febs.15771","article-title":"Signaling and function of cardiac autonomic nervous system receptors: Insights from the GPCR signalling universe","volume":"288","author":"Lymperopoulos","year":"2021","journal-title":"FEBS J."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nrcardio.2016.163","article-title":"Neurohormonal activation in heart failure with reduced ejection fraction","volume":"14","author":"Hartupee","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1056\/NEJM198409273111303","article-title":"Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure","volume":"311","author":"Cohn","year":"1984","journal-title":"N. Engl. J. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1161\/01.CIR.90.1.234","article-title":"Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure","volume":"90","author":"Kingwell","year":"1994","journal-title":"Circulation"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1093\/eurheartj\/ehx261","article-title":"IL-18 cleavage triggers cardiac inflammation and fibrosis upon \u03b2-adrenergic insult","volume":"39","author":"Xiao","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1111\/bph.14674","article-title":"Stimulation of \u03b2-adrenoceptors up-regulates cardiac expression of galectin-3 and BIM through the Hippo signalling pathway","volume":"176","author":"Zhao","year":"2019","journal-title":"Br. J. Pharm."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/S0008-6363(00)00187-5","article-title":"Age-dependent cardiomyopathy and heart failure phenotype in mice overexpressing \u03b22-adrenergic receptors in the heart","volume":"48","author":"Du","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"7059","DOI":"10.1073\/pnas.96.12.7059","article-title":"Progressive hypertrophy and heart failure in \u03b21-adrenergic receptor transgenic mice","volume":"96","author":"Engelhardt","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1161\/01.CIR.101.14.1707","article-title":"Early and delayed consequences of \u03b22-adrenergic receptor overexpression in mouse hearts: Critical role for expression level","volume":"101","author":"Liggett","year":"2000","journal-title":"Circulation"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1093\/eurheartj\/ehx564","article-title":"Beta-blockers in Heart Failure Collaborative, G. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: An individual patient-level analysis of double-blind randomized trials","volume":"39","author":"Cleland","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1161\/01.CIR.98.12.1184","article-title":"Clinical effects of \u03b2-adrenergic blockade in chronic heart failure: A meta-analysis of double-blind, placebo-controlled, randomized trials","volume":"98","author":"Lechat","year":"1998","journal-title":"Circulation"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1126\/science.1109237","article-title":"Transduction of receptor signals by \u03b2-arrestins","volume":"308","author":"Lefkowitz","year":"2005","journal-title":"Science"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1172\/JCI29576","article-title":"Inhibition of p38\u03b1 MAPK rescues cardiomyopathy induced by overexpressed \u03b22-adrenergic receptor, but not \u03b21-adrenergic receptor","volume":"117","author":"Peter","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.jacbts.2017.12.002","article-title":"Designer Approaches for G Protein-Coupled Receptor Modulation for Cardiovascular Disease","volume":"3","author":"Grisanti","year":"2018","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1161\/01.RES.81.6.1021","article-title":"\u03b2-Arrestin1 knockout mice appear normal but demonstrate altered cardiac responses to \u03b2-adrenergic stimulation","volume":"81","author":"Conner","year":"1997","journal-title":"Circ. Res."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Watari, K., Nakaya, M., Nishida, M., Kim, K.M., and Kurose, H. (2013). \u03b2-arrestin2 in infiltrated macrophages inhibits excessive inflammation after myocardial infarction. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068351"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1161\/HYPERTENSIONAHA.113.02043","article-title":"Negative impact of \u03b2-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms","volume":"63","author":"Dabul","year":"2014","journal-title":"Hypertension"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1161\/HYPERTENSIONAHA.117.09817","article-title":"\u03b2-Arrestin2 Improves Post-Myocardial Infarction Heart Failure via Sarco(endo)plasmic Reticulum Ca2+-ATPase-Dependent Positive Inotropy in Cardiomyocytes","volume":"70","author":"McCrink","year":"2017","journal-title":"Hypertension"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2948","DOI":"10.1016\/j.jacc.2017.10.008","article-title":"Cardiac \u03b2arrestin2 Improves Contractility and Adverse Remodeling in Heart Failure, But Is Underexpressed in Humans","volume":"70","author":"McCrink","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_105","first-page":"I12","article-title":"Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium","volume":"82","author":"Bristow","year":"1990","journal-title":"Circulation"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/BF00795362","article-title":"Role of G-proteins in altered \u03b2-adrenergic responsiveness in the failing and hypertrophied myocardium","volume":"91","author":"Bohm","year":"1996","journal-title":"Basic Res. Cardiol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1161\/01.CIR.93.9.1667","article-title":"Cardiac sympathetic nerve function in congestive heart failure","volume":"93","author":"Eisenhofer","year":"1996","journal-title":"Circulation"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"26L","DOI":"10.1016\/S0002-9149(97)00846-1","article-title":"Mechanism of action of beta-blocking agents in heart failure","volume":"80","author":"Bristow","year":"1997","journal-title":"Am. J. Cardiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1126\/science.1185988","article-title":"\u03b22-adrenergic receptor redistribution in heart failure changes cAMP compartmentation","volume":"327","author":"Nikolaev","year":"2010","journal-title":"Science"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.2217\/pgs.14.120","article-title":"Pharmacogenetics of cardiac inotropy","volume":"15","author":"Lymperopoulos","year":"2014","journal-title":"Pharmacogenomics"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1161\/01.CIR.0000087595.17277.73","article-title":"Enhanced Gi signaling selectively negates \u03b22-adrenergic receptor (AR)--but not \u03b21-AR-mediated positive inotropic effect in myocytes from failing rat hearts","volume":"108","author":"Xiao","year":"2003","journal-title":"Circulation"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1161\/CIRCRESAHA.111.253260","article-title":"Gi-biased \u03b22AR signaling links GRK2 upregulation to heart failure","volume":"110","author":"Zhu","year":"2012","journal-title":"Circ. Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/1478-811X-11-64","article-title":"GRK2 blockade with \u03b2ARKct is essential for cardiac \u03b22-adrenergic receptor signaling towards increased contractility","volume":"11","author":"Salazar","year":"2013","journal-title":"Cell Commun. Signal."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1161\/01.CIR.87.2.454","article-title":"Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart","volume":"87","author":"Ungerer","year":"1993","journal-title":"Circulation"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nm1553","article-title":"Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure","volume":"13","author":"Lymperopoulos","year":"2007","journal-title":"Nat. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1161\/01.CIR.101.1.71","article-title":"\u03b22-adrenergic receptor overexpression exacerbates development of heart failure after aortic stenosis","volume":"101","author":"Du","year":"2000","journal-title":"Circulation"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00395-015-0461-1","article-title":"Mst1 inhibition rescues \u03b21-adrenergic cardiomyopathy by reducing myocyte necrosis and non-myocyte apoptosis rather than myocyte apoptosis","volume":"110","author":"Lee","year":"2015","journal-title":"Basic Res. Cardiol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.neulet.2010.07.040","article-title":"Response inhibition in adolescent earthquake survivors with and without posttraumatic stress disorder: A combined behavioral and ERP study","volume":"486","author":"Wu","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1093\/cvr\/cvt005","article-title":"Spatial control of the \u03b2AR system in heart failure: The transverse tubule and beyond","volume":"98","author":"Gorelik","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_120","first-page":"1209","article-title":"Current and future G protein-coupled receptor signaling targets for heart failure therapy","volume":"7","author":"Dabul","year":"2013","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1111\/j.1476-5381.2010.01043.x","article-title":"Myocardial oxidative stress contributes to transgenic \u03b22-adrenoceptor activation-induced cardiomyopathy and heart failure","volume":"162","author":"Xu","year":"2011","journal-title":"Br. J. Pharm."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0008-6363(00)00065-1","article-title":"\u03b22-adrenergic receptor overexpression driven by \u03b1-MHC promoter is downregulated in hypertrophied and failing myocardium","volume":"47","author":"Sheridan","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"H2456","DOI":"10.1152\/ajpheart.2000.279.5.H2456","article-title":"Preserved ventricular contractility in infarcted mouse heart overexpressing \u03b22-adrenergic receptors","volume":"279","author":"Du","year":"2000","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1161\/CIRCULATIONAHA.112.111591","article-title":"High levels of circulating epinephrine trigger apical cardiodepression in a \u03b22-adrenergic receptor\/Gi-dependent manner: A new model of Takotsubo cardiomyopathy","volume":"126","author":"Paur","year":"2012","journal-title":"Circulation"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/24884","article-title":"Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP","volume":"396","author":"Zwartkruis","year":"1998","journal-title":"Nature"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Bouvet, M., Blondeau, J.P., and Lezoualc\u2019h, F. (2019). The Epac1 Protein: Pharmacological Modulators, Cardiac Signalosome and Pathophysiology. Cells, 8.","DOI":"10.3390\/cells8121543"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1161\/CIRCRESAHA.116.309859","article-title":"Multifunctional Mitochondrial Epac1 Controls Myocardial Cell Death","volume":"120","author":"Fazal","year":"2017","journal-title":"Circ. Res."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Szanda, G., Wisniewski, E., Rajki, A., and Spat, A. (2018). Mitochondrial cAMP exerts positive feedback on mitochondrial Ca2+ uptake via the recruitment of Epac1. J. Cell Sci., 131.","DOI":"10.1242\/jcs.215178"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/s41580-018-0052-8","article-title":"The machineries, regulation and cellular functions of mitochondrial calcium","volume":"19","author":"Giorgi","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1161\/CIRCRESAHA.115.306529","article-title":"Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease","volume":"118","author":"Fazal","year":"2016","journal-title":"Circ. Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1172\/JCI64784","article-title":"Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses","volume":"124","author":"Okumura","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1093\/cvr\/cvu242","article-title":"Exchange protein directly activated by cAMP 1 promotes autophagy during cardiomyocyte hypertrophy","volume":"105","author":"Laurent","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_133","first-page":"1766","article-title":"Identification of a pharmacological inhibitor of Epac1 that protects the heart against acute and chronic models of cardiac stress","volume":"115","author":"Laudette","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1038\/s41467-017-01855-z","article-title":"Galphai is required for carvedilol-induced \u03b21 adrenergic receptor \u03b2-arrestin biased signaling","volume":"8","author":"Wang","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Wang, Q., Wang, Y., West, T.M., Liu, Y., Reddy, G.R., Barbagallo, F., Xu, B., Shi, Q., Deng, B., and Wei, W. (2020). Carvedilol induces biased \u03b21 adrenergic receptor-Nitric oxide synthase 3-cyclic guanylyl monophosphate signaling to promote cardiac contractility. Cardiovasc. Res.","DOI":"10.1093\/cvr\/cvaa266"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1124\/jpet.115.227959","article-title":"Recruitment of \u03b2-arrestin 1 and 2 to the \u03b22-adrenoceptor: Analysis of 65 ligands","volume":"355","author":"Littmann","year":"2015","journal-title":"J. Pharm. Exp."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"O\u2019Hayre, M., Eichel, K., Avino, S., Zhao, X., Steffen, D.J., Feng, X., Kawakami, K., Aoki, J., Messer, K., and Sunahara, R. (2017). Genetic evidence that \u03b2-arrestins are dispensable for the initiation of \u03b22-adrenergic receptor signaling to ERK. Sci. Signal., 10.","DOI":"10.1126\/scisignal.aal3395"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/bs.ircmb.2018.02.007","article-title":"Biased Agonism\/Antagonism of Cardiovascular GPCRs for Heart Failure Therapy","volume":"339","author":"Desimine","year":"2018","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1161\/CIRCRESAHA.118.314322","article-title":"\u03b22-Adrenergic Stimulation Compartmentalizes \u03b21 Signaling Into Nanoscale Local Domains by Targeting the C-Terminus of \u03b21-Adrenoceptors","volume":"124","author":"Yang","year":"2019","journal-title":"Circ. Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.pbiomolbio.2019.06.001","article-title":"Studying \u03b21 and \u03b22 adrenergic receptor signals in cardiac cells using FRET-based sensors","volume":"154","author":"Grisan","year":"2020","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Delaunay, M., Osman, H., Kaiser, S., and Diviani, D. (2019). The Role of Cyclic AMP Signaling in Cardiac Fibrosis. Cells, 9.","DOI":"10.3390\/cells9010069"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/S0008-6363(02)00729-0","article-title":"Chronic \u03b22-adrenergic receptor stimulation increases proliferation of human cardiac fibroblasts via an autocrine mechanism","volume":"57","author":"Turner","year":"2003","journal-title":"Cardiovasc. Res."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1111\/j.1476-5381.2011.01785.x","article-title":"\u03b2-Adrenergic receptors stimulate interleukin-6 production through Epac-dependent activation of PKCdelta\/p38 MAPK signalling in neonatal mouse cardiac fibroblasts","volume":"166","author":"Chen","year":"2012","journal-title":"Br. J. Pharm."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.jacc.2017.06.049","article-title":"Pharmacological and Activated Fibroblast Targeting of G\u03b2\u03b3-GRK2 After Myocardial Ischemia Attenuates Heart Failure Progression","volume":"70","author":"Travers","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.yjmcc.2005.12.005","article-title":"Noncanonical cAMP pathway and p38 MAPK mediate \u03b22-adrenergic receptor-induced IL-6 production in neonatal mouse cardiac fibroblasts","volume":"40","author":"Yin","year":"2006","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/sj.bjp.0707622","article-title":"Knockout of \u03b21- and \u03b22-adrenoceptors attenuates pressure overload-induced cardiac hypertrophy and fibrosis","volume":"153","author":"Kiriazis","year":"2008","journal-title":"Br. J. Pharm."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1111\/j.1476-5381.2012.01847.x","article-title":"cAMP and Epac in the regulation of tissue fibrosis","volume":"166","author":"Insel","year":"2012","journal-title":"Br. J. Pharm."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Pollard, C.M., Desimine, V.L., Wertz, S.L., Perez, A., Parker, B.M., Maning, J., McCrink, K.A., Shehadeh, L.A., and Lymperopoulos, A. (2019). Deletion of Osteopontin Enhances \u03b22-Adrenergic Receptor-Dependent Anti-Fibrotic Signaling in Cardiomyocytes. Int. J. Mol. Sci., 20.","DOI":"10.20944\/preprints201902.0266.v1"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/cvr\/cvm078","article-title":"Cardiac \u03b11-adrenergic drive in pathological remodelling","volume":"77","author":"Woodcock","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1097\/FJC.0000000000000032","article-title":"Alpha-1-adrenergic receptors in heart failure: The adaptive arm of the cardiac response to chronic catecholamine stimulation","volume":"63","author":"Jensen","year":"2014","journal-title":"J. Cardiovasc. Pharm."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1172\/JCI22811","article-title":"\u03b11-adrenergic receptors prevent a maladaptive cardiac response to pressure overload","volume":"116","author":"Swigart","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"H1079","DOI":"10.1152\/ajpheart.2000.279.3.H1079","article-title":"Adverse effects of constitutively active \u03b11B-adrenergic receptors after pressure overload in mouse hearts","volume":"279","author":"Wang","year":"2000","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1161\/CIRCULATIONAHA.106.664862","article-title":"An alpha1A-adrenergic-extracellular signal-regulated kinase survival signaling pathway in cardiac myocytes","volume":"115","author":"Huang","year":"2007","journal-title":"Circulation"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1161\/CIRCRESAHA.118.314416","article-title":"Coupling to Gq Signaling Is Required for Cardioprotection by an Alpha-1A-Adrenergic Receptor Agonist","volume":"125","author":"Myagmar","year":"2019","journal-title":"Circ. Res."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"261","DOI":"10.3109\/10799893.2015.1091475","article-title":"\u03b11A-Adrenergic receptor prevents cardiac ischemic damage through PKCdelta\/GLUT1\/4-mediated glucose uptake","volume":"36","author":"Shi","year":"2016","journal-title":"J. Recept. Signal Transduct. Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1161\/hh1601.095912","article-title":"Targeted \u03b11A-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy","volume":"89","author":"Lin","year":"2001","journal-title":"Circ. Res."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jacbts.2016.10.006","article-title":"An Oral Selective Alpha-1A Adrenergic Receptor Agonist Prevents Doxorubicin Cardiotoxicity","volume":"2","author":"Beak","year":"2017","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Montgomery, M.D., Chan, T., Swigart, P.M., Myagmar, B.E., Dash, R., and Simpson, P.C. (2017). An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0168409"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1161\/CIRCHEARTFAILURE.108.846212","article-title":"\u03b11-Adrenergic receptor subtypes in nonfailing and failing human myocardium","volume":"2","author":"Jensen","year":"2009","journal-title":"Circ. Heart Fail."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/FJC.0000000000000604","article-title":"Human Myocardium Has a Robust \u03b11A-Subtype Adrenergic Receptor Inotropic Response","volume":"72","author":"Janssen","year":"2018","journal-title":"J. Cardiovasc. Pharm."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Yu, Z.Y., Tan, J.C., McMahon, A.C., Iismaa, S.E., Xiao, X.H., Kesteven, S.H., Reichelt, M.E., Mohl, M.C., Smith, N.J., and Fatkin, D. (2014). RhoA\/ROCK signaling and pleiotropic \u03b11A-adrenergic receptor regulation of cardiac contractility. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099024"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1093\/cvr\/cvr081","article-title":"Regulation of murine cardiac contractility by activation of \u03b11A-adrenergic receptor-operated Ca2+ entry","volume":"91","author":"Mohl","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/46040","article-title":"Two functionally distinct \u03b12-adrenergic receptors regulate sympathetic neurotransmission","volume":"402","author":"Hein","year":"1999","journal-title":"Nature"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1161\/01.CIR.0000036600.39600.66","article-title":"Feedback inhibition of catecholamine release by two different \u03b12-adrenoceptor subtypes prevents progression of heart failure","volume":"106","author":"Brede","year":"2002","journal-title":"Circulation"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1210\/me.2003-0035","article-title":"Differential control of adrenal and sympathetic catecholamine release by \u03b12-adrenoceptor subtypes","volume":"17","author":"Brede","year":"2003","journal-title":"Mol. Endocrinol."},{"key":"ref_166","first-page":"343","article-title":"\u03b12-adrenergic receptor subtypes-novel functions uncovered in gene-targeted mouse models","volume":"96","author":"Brede","year":"2004","journal-title":"Biol. Cell"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"16378","DOI":"10.1074\/jbc.M109.077859","article-title":"Reduction of sympathetic activity via adrenal-targeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction","volume":"285","author":"Lymperopoulos","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1210\/me.2015-1305","article-title":"GRK2 Up-Regulation Creates a Positive Feedback Loop for Catecholamine Production in Chromaffin Cells","volume":"30","author":"Jafferjee","year":"2016","journal-title":"Mol. Endocrinol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s00395-011-0166-z","article-title":"Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis","volume":"106","author":"Schneider","year":"2011","journal-title":"Basic Res. Cardiol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1478-811X-9-5","article-title":"Impaired desensitization of a human polymorphic \u03b12B-adrenergic receptor variant enhances its sympatho-inhibitory activity in chromaffin cells","volume":"9","author":"Nguyen","year":"2011","journal-title":"Cell Commun. Signal."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1056\/NEJMoa020803","article-title":"Synergistic polymorphisms of beta1- and alpha2C-adrenergic receptors and the risk of congestive heart failure","volume":"347","author":"Small","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"O\u2019Connor, C.M., Fiuzat, M., Carson, P.E., Anand, I.S., Plehn, J.F., Gottlieb, S.S., Silver, M.A., Lindenfeld, J., Miller, A.B., and White, M. (2012). Combinatorial pharmacogenetic interactions of bucindolol and \u03b21, \u03b12C adrenergic receptor polymorphisms. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044324"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"200","DOI":"10.4330\/wjc.v9.i3.200","article-title":"Angiotensin receptor blocker drugs and inhibition of adrenal \u03b2-arrestin-1-dependent aldosterone production: Implications for heart failure therapy","volume":"9","author":"Lymperopoulos","year":"2017","journal-title":"World J. Cardiol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1124\/pr.109.002436","article-title":"Beyond desensitization: Physiological relevance of arrestin-dependent signaling","volume":"62","author":"Luttrell","year":"2010","journal-title":"Pharm. Rev."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.jacc.2010.08.635","article-title":"Adrenal \u03b2-arrestin 1 inhibition in vivo attenuates post-myocardial infarction progression to heart failure and adverse remodeling via reduction of circulating aldosterone levels","volume":"57","author":"Lymperopoulos","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"5825","DOI":"10.1073\/pnas.0811706106","article-title":"An adrenal \u03b2-arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo","volume":"106","author":"Lymperopoulos","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Pollard, C.M., Ghandour, J., Cora, N., Perez, A., Parker, B.M., Desimine, V.L., Wertz, S.L., Pereyra, J.M., Ferraino, K.E., and Patel, J.J. (2020). GRK2-Mediated Crosstalk between \u03b2-Adrenergic and Angiotensin II Receptors Enhances Adrenocortical Aldosterone Production In Vitro and In Vivo. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21020574"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"192","DOI":"10.4330\/wjc.v12.i5.192","article-title":"Nicotine-induced adrenal \u03b2-arrestin1 upregulation mediates tobacco-related hyperaldosteronism leading to cardiac dysfunction","volume":"12","author":"Cora","year":"2020","journal-title":"World J. Cardiol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"109967","DOI":"10.1016\/j.cellsig.2021.109967","article-title":"Adrenal angiotensin II type 1 receptor biased signaling: The case for \"biased\" inverse agonism for effective aldosterone suppression","volume":"82","author":"Ferraino","year":"2021","journal-title":"Cell Signal."},{"key":"ref_180","doi-asserted-by":"crossref","unstructured":"Maning, J., McCrink, K.A., Pollard, C.M., Desimine, V.L., Ghandour, J., Perez, A., Cora, N., Ferraino, K.E., Parker, B.M., and Brill, A.R. (2020). Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082868"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1152\/physrev.00015.2014","article-title":"The evolving impact of g protein-coupled receptor kinases in cardiac health and disease","volume":"95","author":"Sato","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Marzano, F., Rapacciuolo, A., Ferrara, N., Rengo, G., Koch, W.J., and Cannavo, A. (2021). Targeting GRK5 for Treating Chronic Degenerative Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041920"},{"key":"ref_183","doi-asserted-by":"crossref","unstructured":"Coleman, R.C., Eguchi, A., Lieu, M., Roy, R., Barr, E.W., Ibetti, J., Lucchese, A.M., Peluzzo, A.M., Gresham, K., and Chuprun, J.K. (2021). A peptide of the N terminus of GRK5 attenuates pressure-overload hypertrophy and heart failure. Sci. Signal., 14.","DOI":"10.1126\/scisignal.abb5968"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/nm1750","article-title":"A GRK5 polymorphism that inhibits \u03b2-adrenergic receptor signaling is protective in heart failure","volume":"14","author":"Liggett","year":"2008","journal-title":"Nat. Med."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1161\/ATVBAHA.111.239608","article-title":"G protein-coupled receptor kinase-5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7-transmembrane receptors","volume":"32","author":"Wu","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"H368","DOI":"10.1152\/ajpheart.01061.2011","article-title":"Different expression of adrenoceptors and GRKs in the human myocardium depends on heart failure etiology and correlates to clinical variables","volume":"303","author":"Monto","year":"2012","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"17818","DOI":"10.1073\/pnas.0804446105","article-title":"The G-protein-coupled receptor kinase 5 inhibits NF\u03baB transcriptional activity by inducing nuclear accumulation of I\u03baB\u03b1","volume":"105","author":"Sorriento","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_188","doi-asserted-by":"crossref","unstructured":"de Lucia, C., Grisanti, L.A., Borghetti, G., Piedepalumbo, M., Ibetti, J., Maria Lucchese, A., Barr, E.W., Roy, R., Dedo Okyere, A., and Christine Murphy, H. (2021). GRK5 contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure. Cardiovasc. Res.","DOI":"10.1093\/cvr\/cvab044"},{"key":"ref_189","doi-asserted-by":"crossref","unstructured":"Eguchi, A., Coleman, R., Gresham, K., Gao, E., Ibetti, J., Chuprun, J.K., and Koch, W.J. (2021). GRK5 is a regulator of fibroblast activation and cardiac fibrosis. Proc. Natl. Acad. Sci. USA, 118.","DOI":"10.1073\/pnas.2012854118"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"15895","DOI":"10.1073\/pnas.1818547116","article-title":"Perturbation of the interactions of calmodulin with GRK5 using a natural product chemical probe","volume":"116","author":"Beyett","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_191","doi-asserted-by":"crossref","unstructured":"Pabbidi, M.R., Ji, X., Maxwell, J.T., Mignery, G.A., Samarel, A.M., and Lipsius, S.L. (2016). Inhibition of cAMP-Dependent PKA Activates \u03b22-Adrenergic Receptor Stimulation of Cytosolic Phospholipase A2 via Raf-1\/MEK\/ERK and IP3-Dependent Ca2+ Signaling in Atrial Myocytes. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168505"},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1248\/bpb.b17-00291","article-title":"The Aldosterone Receptor Antagonist Eplerenone Inhibits Isoproterenol-Induced Collagen-I and 11\u03b2-HSD1 Expression in Rat Cardiac Fibroblasts and the Left Ventricle","volume":"40","author":"Hori","year":"2017","journal-title":"Biol. Pharm. Bull."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1096\/fj.09-146985","article-title":"Mineralocorticoid receptor inhibits CREB signaling by calcineurin activation","volume":"24","author":"Grossmann","year":"2010","journal-title":"FASEB J."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"109446","DOI":"10.1016\/j.cellsig.2019.109446","article-title":"Sustained GRK2-dependent CREB activation is essential for \u03b12-adrenergic receptor-induced PC12 neuronal differentiation","volume":"66","author":"Karkoulias","year":"2020","journal-title":"Cell Signal."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.cardiores.2006.02.010","article-title":"Cross talk between corticosteroids and alpha-adrenergic signalling augments cardiomyocyte hypertrophy: A possible role for SGK1","volume":"70","author":"Lister","year":"2006","journal-title":"Cardiovasc. Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/6\/1552\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:19:14Z","timestamp":1760163554000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/6\/1552"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,19]]},"references-count":195,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["cells10061552"],"URL":"https:\/\/doi.org\/10.3390\/cells10061552","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,19]]}}}