{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:27:55Z","timestamp":1789464475243,"version":"build-2803163510"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,4,20]],"date-time":"2017-04-20T00:00:00Z","timestamp":1492646400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,4,20]],"date-time":"2017-04-20T00:00:00Z","timestamp":1492646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The valosin-containing protein (VCP) participates in signaling pathways essential for cell homeostasis in multiple tissues, however, its function in the heart <jats:italic>in vivo<\/jats:italic> remains unknown. Here we offer the first description of the expression, function and mechanism of action of VCP in the mammalian heart <jats:italic>in vivo<\/jats:italic> in both normal and stress conditions. By using a transgenic (TG) mouse with cardiac-specific overexpression (3.5-fold) of VCP, we demonstrate that VCP is a new and powerful mediator of cardiac protection against cell death <jats:italic>in vivo<\/jats:italic>, as evidenced by a 50% reduction of infarct size after ischemia\/reperfusion versus wild type. We also identify a novel role of VCP in preserving mitochondrial respiration and in preventing the opening of mitochondrial permeability transition pore in cardiac myocytes under stress. In particular, by genetic deletion of inducible isoform of nitric oxide synthase (iNOS) from VCP TG mouse and by pharmacological inhibition of iNOS in isolated cardiac myocytes, we reveal that an increase of expression and activity of iNOS in cardiomyocytes by VCP is an essential mechanistic link of VCP-mediated preservation of mitochondrial function. These data together demonstrate that VCP may represent a novel therapeutic avenue for the prevention of myocardial ischemia.<\/jats:p>","DOI":"10.1038\/srep46324","type":"journal-article","created":{"date-parts":[[2017,4,20]],"date-time":"2017-04-20T09:48:51Z","timestamp":1492681731000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["The valosin-containing protein is a novel mediator of mitochondrial respiration and cell survival in the heart in vivo"],"prefix":"10.1038","volume":"7","author":[{"given":"Paulo","family":"Lizano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman","family":"Rashed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaunrick","family":"Stoll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairuo","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristan T.","family":"Hays","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gangjian","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lai-Hua","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Depre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,20]]},"reference":[{"key":"BFsrep46324_CR1","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1161\/circ.131.suppl_2.o29","volume":"131","author":"D Mozaffarian","year":"2015","unstructured":"Mozaffarian, D. et al. Heart disease and stroke statistics\u20132015 update: a report from the American Heart Association. Circulation 131, e29\u2013322 (2015).","journal-title":"Circulation"},{"key":"BFsrep46324_CR2","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1006\/jmcc.2001.1378","volume":"33","author":"EJ Lesnefsky","year":"2001","unstructured":"Lesnefsky, E. J., Moghaddas, S., Tandler, B., Kerner, J. & Hoppel, C. L. Mitochondrial dysfunction in cardiac disease: ischemia\u2013reperfusion, aging, and heart failure. J Mol Cell Cardiol 33, 1065\u20131089 (2001).","journal-title":"J Mol Cell Cardiol"},{"key":"BFsrep46324_CR3","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.yjmcc.2014.11.005","volume":"78","author":"SB Ong","year":"2015","unstructured":"Ong, S. B., Samangouei, P., Kalkhoran, S. B. & Hausenloy, D. J. The mitochondrial permeability transition pore and its role in myocardial ischemia reperfusion injury. J Mol Cell Cardiol 78, 23\u201334 (2015).","journal-title":"J Mol Cell Cardiol"},{"key":"BFsrep46324_CR4","doi-asserted-by":"crossref","first-page":"H1","DOI":"10.1152\/ajpheart.00747.2013","volume":"307","author":"JM Hollander","year":"2014","unstructured":"Hollander, J. M., Thapa, D. & Shepherd, D. L. Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies. Am J Physiol Heart Circ Physiol 307, H1\u201314 (2014).","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"BFsrep46324_CR5","doi-asserted-by":"crossref","first-page":"100","DOI":"10.4330\/wjc.v6.i3.100","volume":"6","author":"A Dominguez-Rodriguez","year":"2014","unstructured":"Dominguez-Rodriguez, A., Abreu-Gonzalez, P. & Reiter, R. J. Cardioprotection and pharmacological therapies in acute myocardial infarction: Challenges in the current era. World J Cardiol 6, 100\u2013106 (2014).","journal-title":"World J Cardiol"},{"key":"BFsrep46324_CR6","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1067\/msy.2002.119490","volume":"131","author":"JA Crestanello","year":"2002","unstructured":"Crestanello, J. A. et al. Mitochondrial function during ischemic preconditioning. Surgery 131, 172\u2013178 (2002).","journal-title":"Surgery"},{"key":"BFsrep46324_CR7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.exger.2011.11.001","volume":"47","author":"AP Wojtovich","year":"2012","unstructured":"Wojtovich, A. P., Nadtochiy, S. M., Brookes, P. S. & Nehrke, K. Ischemic preconditioning: the role of mitochondria and aging. Exp Gerontol 47, 1\u20137 (2012).","journal-title":"Exp Gerontol"},{"key":"BFsrep46324_CR8","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1089\/ars.2007.1845","volume":"10","author":"LS Burwell","year":"2008","unstructured":"Burwell, L. S. & Brookes, P. S. Mitochondria as a target for the cardioprotective effects of nitric oxide in ischemia-reperfusion injury. Antioxid Redox Signal 10, 579\u2013599 (2008).","journal-title":"Antioxid Redox Signal"},{"key":"BFsrep46324_CR9","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1006\/jmcc.2002.2066","volume":"34","author":"LH Opie","year":"2002","unstructured":"Opie, L. H. & Sack, M. N. Metabolic plasticity and the promotion of cardiac protection in ischemia and ischemic preconditioning. J Mol Cell Cardiol 34, 1077\u20131089 (2002).","journal-title":"J Mol Cell Cardiol"},{"key":"BFsrep46324_CR10","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.mito.2011.06.001","volume":"11","author":"B Kadenbach","year":"2011","unstructured":"Kadenbach, B., Ramzan, R., Moosdorf, R. & Vogt, S. The role of mitochondrial membrane potential in ischemic heart failure. Mitochondrion 11, 700\u2013706 (2011).","journal-title":"Mitochondrion"},{"key":"BFsrep46324_CR11","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0163-7258(00)00102-9","volume":"89","author":"MS Suleiman","year":"2001","unstructured":"Suleiman, M. S., Halestrap, A. P. & Griffiths, E. J. Mitochondria: a target for myocardial protection. Pharmacol Ther 89, 29\u201346 (2001).","journal-title":"Pharmacol Ther"},{"key":"BFsrep46324_CR12","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.1111\/bph.13013","volume":"172","author":"SB Ong","year":"2015","unstructured":"Ong, S. B., Dongworth, R. K., Cabrera-Fuentes, H. A. & Hausenloy, D. J. Role of the MPTP in conditioning the heart - translatability and mechanism. Br J Pharmacol 172, 2074\u20132084 (2015).","journal-title":"Br J Pharmacol"},{"key":"BFsrep46324_CR13","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.yjmcc.2014.09.023","volume":"78","author":"P Bernardi","year":"2015","unstructured":"Bernardi, P. & Di Lisa, F. The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection. J Mol Cell Cardiol 78, 100\u2013106 (2015).","journal-title":"J Mol Cell Cardiol"},{"key":"BFsrep46324_CR14","unstructured":"Halestrap, A. P. & Richardson, A. P. The mitochondrial permeability transition: a current (2015)."},{"key":"BFsrep46324_CR15","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1093\/cvr\/cvt136","volume":"99","author":"P Lizano","year":"2013","unstructured":"Lizano, P. et al. The valosin-containing protein promotes cardiac survival through the inducible isoform of nitric oxide synthase. Cardiovasc Res 99, 685\u2013693 (2013).","journal-title":"Cardiovasc Res"},{"key":"BFsrep46324_CR16","doi-asserted-by":"crossref","first-page":"H19","DOI":"10.1152\/ajpheart.00712.2006","volume":"292","author":"R Bolli","year":"2007","unstructured":"Bolli, R. Preconditioning: a paradigm shift in the biology of myocardial ischemia. Am J Physiol Heart Circ Physiol 292, H19\u201327 (2007).","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"BFsrep46324_CR17","first-page":"1094","volume":"81","author":"R Bolli","year":"1997","unstructured":"Bolli, R. et al. The protective effect of late preconditioning against myocardial stunning in conscious rabbits is mediated by nitric oxide synthase. Evidence that nitric oxide acts both as a trigger and as a mediator of the late phase of ischemic preconditioning. Circ Res 81, 1094\u20131107 (1997).","journal-title":"Evidence that nitric oxide acts both as a trigger and as a mediator of the late phase of ischemic preconditioning. Circ Res"},{"key":"BFsrep46324_CR18","doi-asserted-by":"crossref","first-page":"e0119537","DOI":"10.1371\/journal.pone.0119537","volume":"10","author":"E Rashed","year":"2015","unstructured":"Rashed, E. et al. Heat Shock Protein 22 (Hsp22) Regulates Oxidative Phosphorylation upon Its Mitochondrial Translocation with the Inducible Nitric Oxide Synthase in Mammalian Heart. PloS one 10, e0119537 (2015).","journal-title":"PloS one"},{"key":"BFsrep46324_CR19","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jsb.2006.01.005","volume":"156","author":"Y Ye","year":"2006","unstructured":"Ye, Y. Diverse functions with a common regulator: ubiquitin takes command of an AAA ATPase. J Struct Biol 156, 29\u201340, doi:S1047-8477 (2006).","journal-title":"J Struct Biol"},{"key":"BFsrep46324_CR20","doi-asserted-by":"crossref","first-page":"3533","DOI":"10.1002\/j.1460-2075.1992.tb05436.x","volume":"11","author":"M Egerton","year":"1992","unstructured":"Egerton, M. et al. VCP, the mammalian homolog of cdc48, is tyrosine phosphorylated in response to T cell antigen receptor activation. EMBO J 11, 3533\u20133540 (1992).","journal-title":"EMBO J"},{"key":"BFsrep46324_CR21","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/365459a0","volume":"365","author":"IT Pleasure","year":"1993","unstructured":"Pleasure, I. T., Black, M. M. & Keen, J. H. Valosin-containing protein, VCP, is a ubiquitous clathrin-binding protein. Nature 365, 459\u2013462 (1993).","journal-title":"Nature"},{"key":"BFsrep46324_CR22","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1128\/MCB.22.2.626-634.2002","volume":"22","author":"E Rabinovich","year":"2002","unstructured":"Rabinovich, E., Kerem, A., Frohlich, K. U., Diamant, N. & Bar-Nun, S. AAA-ATPase p97\/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol Cell Biol 22, 626\u2013634 (2002).","journal-title":"Mol Cell Biol"},{"key":"BFsrep46324_CR23","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0962-8924(97)01212-9","volume":"8","author":"S Patel","year":"1998","unstructured":"Patel, S. & Latterich, M. The AAA team: related ATPases with diverse functions. Trends Cell Biol 8, 65\u201371 (1998).","journal-title":"Trends Cell Biol"},{"key":"BFsrep46324_CR24","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.jacc.2015.02.032","volume":"65","author":"B Ibanez","year":"2015","unstructured":"Ibanez, B., Heusch, G., Ovize, M. & Van de Werf, F. Evolving Therapies for Myocardial Ischemia\/Reperfusion Injury. J Am Coll Cardiol 65, 1454\u20131471 (2015).","journal-title":"J Am Coll Cardiol"},{"key":"BFsrep46324_CR25","first-page":"e514","volume":"168","author":"AR Khan","year":"2014","unstructured":"Khan, A. R. et al. Cardioprotective role of ischemic postconditioning in acute myocardial infarction: a systematic review and meta-analysis. Am Heart J 168, 512-521 e514 (2014).","journal-title":"Am Heart J"},{"key":"BFsrep46324_CR26","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1016\/j.bbamcr.2008.01.015","volume":"1783","author":"RJ Braun","year":"2008","unstructured":"Braun, R. J. & Zischka, H. Mechanisms of Cdc48\/VCP-mediated cell death: from yeast apoptosis to human disease. Biochim Biophys Acta 1783, 1418\u20131435 (2008).","journal-title":"Biochim Biophys Acta"},{"key":"BFsrep46324_CR27","doi-asserted-by":"crossref","first-page":"17725","DOI":"10.18632\/oncotarget.3918","volume":"6","author":"PP Shah","year":"2015","unstructured":"Shah, P. P. & Beverly, L. J. Regulation of VCP\/p97 demonstrates the critical balance between cell death and epithelial-mesenchymal transition (EMT) downstream of ER stress. Oncotarget 6, 17725\u201317737 (2015).","journal-title":"Oncotarget"},{"key":"BFsrep46324_CR28","doi-asserted-by":"crossref","first-page":"25757","DOI":"10.1074\/jbc.M513699200","volume":"281","author":"RJ Braun","year":"2006","unstructured":"Braun, R. J. et al. Crucial mitochondrial impairment upon CDC48 mutation in apoptotic yeast. J Biol Chem 281, 25757\u201325767 (2006).","journal-title":"J Biol Chem"},{"key":"BFsrep46324_CR29","doi-asserted-by":"crossref","first-page":"51376","DOI":"10.1074\/jbc.M406683200","volume":"279","author":"S Ishigaki","year":"2004","unstructured":"Ishigaki, S. et al. Physical and functional interaction between Dorfin and Valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders. J Biol Chem 279, 51376\u201351385 (2004).","journal-title":"J Biol Chem"},{"key":"BFsrep46324_CR30","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S0304-3940(03)00280-5","volume":"343","author":"Y Mizuno","year":"2003","unstructured":"Mizuno, Y., Hori, S., Kakizuka, A. & Okamoto, K. Vacuole-creating protein in neurodegenerative diseases in humans. Neurosci Lett 343, 77\u201380 (2003).","journal-title":"Neurosci Lett"},{"key":"BFsrep46324_CR31","doi-asserted-by":"crossref","first-page":"3007","DOI":"10.1158\/1078-0432.CCR-03-0191","volume":"10","author":"Y Tsujimoto","year":"2004","unstructured":"Tsujimoto, Y. et al. Elevated expression of valosin-containing protein (p97) is associated with poor prognosis of prostate cancer. Clin Cancer Res 10, 3007\u20133012 (2004).","journal-title":"Clin Cancer Res"},{"key":"BFsrep46324_CR32","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1245\/ASO.2004.10.018","volume":"11","author":"S Yamamoto","year":"2004","unstructured":"Yamamoto, S. et al. Expression level of valosin-containing protein (p97) is correlated with progression and prognosis of non-small-cell lung carcinoma. Ann Surg Oncol 11, 697\u2013704 (2004).","journal-title":"Ann Surg Oncol"},{"key":"BFsrep46324_CR33","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1200\/JCO.2003.06.068","volume":"21","author":"S Yamamoto","year":"2003","unstructured":"Yamamoto, S. et al. Elevated expression of valosin-containing protein (p97) in hepatocellular carcinoma is correlated with increased incidence of tumor recurrence. J Clin Oncol 21, 447\u2013452 (2003).","journal-title":"J Clin Oncol"},{"key":"BFsrep46324_CR34","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1245\/ASO.2005.07.002","volume":"12","author":"S Yamamoto","year":"2005","unstructured":"Yamamoto, S. et al. Increased expression of valosin-containing protein (p97) is correlated with disease recurrence in follicular thyroid cancer. Ann Surg Oncol 12, 925\u2013934, doi: 10.1245\/ASO.2005.07.002 (2005).","journal-title":"Ann Surg Oncol"},{"key":"BFsrep46324_CR35","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1083\/jcb.200903024","volume":"187","author":"PJ Lim","year":"2009","unstructured":"Lim, P. J. et al. Ubiquilin and p97\/VCP bind erasin, forming a complex involved in ERAD. J Cell Biol 187, 201\u2013217 (2009).","journal-title":"J Cell Biol"},{"key":"BFsrep46324_CR36","doi-asserted-by":"crossref","unstructured":"Jarosch, E. et al. Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat Cell Biol 4 (2002).","DOI":"10.1038\/ncb746"},{"key":"BFsrep46324_CR37","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3389\/fncel.2015.00016","volume":"9","author":"L Fang","year":"2015","unstructured":"Fang, L. et al. Mitochondrial function in neuronal cells depends on p97\/VCP\/Cdc48-mediated quality control. Front Cell Neurosci 9, 16 (2015).","journal-title":"Front Cell Neurosci"},{"key":"BFsrep46324_CR38","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1091\/mbc.e10-09-0748","volume":"22","author":"S Xu","year":"2011","unstructured":"Xu, S., Peng, G., Wang, Y., Fang, S. & Karbowski, M. The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover. Mol Biol Cell 22, 291\u2013300 (2011).","journal-title":"Mol Biol Cell"},{"key":"BFsrep46324_CR39","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.neuron.2013.02.028","volume":"78","author":"F Bartolome","year":"2013","unstructured":"Bartolome, F. et al. Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron 78, 57\u201364 (2013).","journal-title":"Neuron"},{"key":"BFsrep46324_CR40","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1042\/bj3410233","volume":"341","author":"M Crompton","year":"1999","unstructured":"Crompton, M. The mitochondrial permeability transition pore and its role in cell death. Biochem J 341 (Pt 2), 233\u2013249 (1999).","journal-title":"Biochem J"},{"key":"BFsrep46324_CR41","first-page":"153","volume":"16","author":"F Orzi","year":"2001","unstructured":"Orzi, F., Castri, P. & Fornai, F. Apomorphine as a neuroprotective drug: a study in MPTP-treated mice and potential relevance to ischemia. Funct Neurol 16, 153\u2013158 (2001).","journal-title":"Funct Neurol"},{"key":"BFsrep46324_CR42","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1161\/CIRCULATIONAHA.108.791533","volume":"118","author":"MB West","year":"2008","unstructured":"West, M. B. et al. Cardiac myocyte-specific expression of inducible nitric oxide synthase protects against ischemia\/reperfusion injury by preventing mitochondrial permeability transition. Circulation 118, 1970\u20131978 (2008).","journal-title":"Circulation"},{"key":"BFsrep46324_CR43","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1038\/sj.bjp.0705080","volume":"138","author":"P Ferdinandy","year":"2003","unstructured":"Ferdinandy, P. & Schulz, R. Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia-reperfusion injury and preconditioning. Br J Pharmacol 138, 532\u2013543 (2003).","journal-title":"Br J Pharmacol"},{"key":"BFsrep46324_CR44","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1172\/JCI0213265","volume":"109","author":"IN Mungrue","year":"2002","unstructured":"Mungrue, I. N. et al. Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest 109, 735\u2013743 (2002).","journal-title":"J Clin Invest"},{"key":"BFsrep46324_CR45","doi-asserted-by":"crossref","first-page":"C112","DOI":"10.1152\/ajpcell.1998.274.1.C112","volume":"274","author":"JJ Poderoso","year":"1998","unstructured":"Poderoso, J. J. et al. Nitric oxide regulates oxygen uptake and hydrogen peroxide release by the isolated beating rat heart. The American journal of physiology 274, C112\u2013119 (1998).","journal-title":"The American journal of physiology"},{"key":"BFsrep46324_CR46","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1097\/01.shk.0000156672.36439.2d","volume":"23","author":"V Borutaite","year":"2005","unstructured":"Borutaite, V., Moncada, S. & Brown, G. C. Nitric oxide from inducible nitric oxide synthase sensitizes the inflamed aorta to hypoxic damage via respiratory inhibition. Shock 23, 319\u2013323 (2005).","journal-title":"Shock"},{"key":"BFsrep46324_CR47","doi-asserted-by":"crossref","first-page":"H47","DOI":"10.1152\/ajpheart.00730.2003","volume":"286","author":"W Li","year":"2004","unstructured":"Li, W., Jue, T., Edwards, J., Wang, X. & Hintze, T. H. Changes in NO bioavailability regulate cardiac O2 consumption: control by intramitochondrial SOD2 and intracellular myoglobin. Am J Physiol Heart Circ Physiol 286, H47\u201354 (2004).","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"BFsrep46324_CR48","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1097\/SHK.0b013e31827f565b","volume":"39","author":"BW Roberts","year":"2013","unstructured":"Roberts, B. W., Mitchell, J., Kilgannon, J. H., Chansky, M. E. & Trzeciak, S. Nitric oxide donor agents for the treatment of ischemia\/reperfusion injury in human subjects: a systematic review. Shock 39, 229\u2013239 (2013).","journal-title":"Shock"},{"key":"BFsrep46324_CR49","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1161\/CIRCULATIONAHA.110.013847","volume":"124","author":"H Qiu","year":"2011","unstructured":"Qiu, H. et al. H11 kinase\/heat shock protein 22 deletion impairs both nuclear and mitochondrial functions of STAT3 and accelerates the transition into heart failure on cardiac overload. Circulation 124, 406\u2013415 (2011).","journal-title":"Circulation"},{"key":"BFsrep46324_CR50","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1006\/jmcc.2001.1482","volume":"34","author":"Y Wang","year":"2002","unstructured":"Wang, Y. et al. Ischemic preconditioning upregulates inducible nitric oxide synthase in cardiac myocyte. J Mol Cell Cardiol 34, 5\u201315 (2002).","journal-title":"J Mol Cell Cardiol"},{"key":"BFsrep46324_CR51","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/0003-9861(92)90433-W","volume":"298","author":"H Ischiropoulos","year":"1992","unstructured":"Ischiropoulos, H., Zhu, L. & Beckman, J. S. Peroxynitrite formation from macrophage-derived nitric oxide. Arch Biochem Biophys 298, 446\u2013451 (1992).","journal-title":"Arch Biochem Biophys"},{"key":"BFsrep46324_CR52","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s00395-012-0253-9","volume":"107","author":"Y Guo","year":"2012","unstructured":"Guo, Y. et al. Identification of inducible nitric oxide synthase in peripheral blood cells as a mediator of myocardial ischemia\/reperfusion injury. Basic Res Cardiol 107, 253 (2012).","journal-title":"Basic Res Cardiol"},{"key":"BFsrep46324_CR53","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1161\/01.RES.0000044380.54893.4B","volume":"91","author":"C Depre","year":"2002","unstructured":"Depre, C. et al. H11 kinase is a novel mediator of myocardial hypertrophy in vivo . Circ Res 91, 1007\u20131014 (2002).","journal-title":"Circ Res"},{"key":"BFsrep46324_CR54","doi-asserted-by":"crossref","first-page":"22157","DOI":"10.1074\/jbc.M710459200","volume":"283","author":"H Qiu","year":"2008","unstructured":"Qiu, H. et al. Characterization of a novel cardiac isoform of the cell cycle-related kinase that is regulated during heart failure. J Biol Chem 283, 22157\u201322165 (2008).","journal-title":"J Biol Chem"},{"key":"BFsrep46324_CR55","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1161\/01.RES.0000201284.45482.e8","volume":"98","author":"C Depre","year":"2006","unstructured":"Depre, C. et al. H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart. Circ Res 98, 280\u2013288 (2006).","journal-title":"Circ Res"},{"key":"BFsrep46324_CR56","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/S0076-6879(09)05020-4","volume":"457","author":"IR Lanza","year":"2009","unstructured":"Lanza, I. R. & Nair, K. S. Functional assessment of isolated mitochondria in vitro . Methods in enzymology 457, 349\u2013372 (2009).","journal-title":"Methods in enzymology"},{"key":"BFsrep46324_CR57","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1161\/CIRCRESAHA.109.206631","volume":"106","author":"JD Turner","year":"2010","unstructured":"Turner, J. D., Gaspers, L. D., Wang, G. & Thomas, A. P. Uncoupling protein-2 modulates myocardial excitation-contraction coupling. Circ Res 106, 730\u2013738 (2010).","journal-title":"Circ Res"},{"key":"BFsrep46324_CR58","doi-asserted-by":"crossref","first-page":"914","DOI":"10.18632\/aging.100252","volume":"2","author":"AV Hafner","year":"2010","unstructured":"Hafner, A. V. et al. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging 2, 914\u2013923 (2010).","journal-title":"Aging"},{"key":"BFsrep46324_CR59","doi-asserted-by":"crossref","first-page":"e80574","DOI":"10.1371\/journal.pone.0080574","volume":"8","author":"Z Zhao","year":"2013","unstructured":"Zhao, Z. et al. Modulation of intracellular calcium waves and triggered activities by mitochondrial ca flux in mouse cardiomyocytes. PloS one 8, e80574 (2013).","journal-title":"PloS one"},{"key":"BFsrep46324_CR60","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.yjmcc.2013.01.003","volume":"58","author":"T Shahzad","year":"2013","unstructured":"Shahzad, T. et al. Mechanisms involved in postconditioning protection of cardiomyocytes against acute reperfusion injury. J Mol Cell Cardiol 58, 209\u2013216 (2013).","journal-title":"J Mol Cell Cardiol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep46324.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep46324","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/srep46324","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/www.nature.com\/articles\/srep46324.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T18:02:27Z","timestamp":1671818547000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep46324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,20]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,6,30]]}},"alternative-id":["BFsrep46324"],"URL":"https:\/\/doi.org\/10.1038\/srep46324","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,20]]},"assertion":[{"value":"28 January 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 April 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"46324"}}