{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:42:53Z","timestamp":1790844173707,"version":"4.1.0"},"reference-count":118,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2019,5,1]],"date-time":"2019-05-01T00:00:00Z","timestamp":1556668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007388","name":"Compagnia di San Paolo","doi-asserted-by":"publisher","award":["ID ROL 17290"],"award-info":[{"award-number":["ID ROL 17290"]}],"id":[{"id":"10.13039\/100007388","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["\"Ricerca Corrente 2018\""],"award-info":[{"award-number":["\"Ricerca Corrente 2018\""]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiac hypertrophy is an adaptive and compensatory mechanism preserving cardiac output during detrimental stimuli. Nevertheless, long-term stimuli incite chronic hypertrophy and may lead to heart failure. In this review, we analyze the recent literature regarding the role of ERK (extracellular signal-regulated kinase) activity in cardiac hypertrophy. ERK signaling produces beneficial effects during the early phase of chronic pressure overload in response to G protein-coupled receptors (GPCRs) and integrin stimulation. These functions comprise (i) adaptive concentric hypertrophy and (ii) cell death prevention. On the other hand, ERK participates in maladaptive hypertrophy during hypertension and chemotherapy-mediated cardiac side effects. Specific ERK-associated scaffold proteins are implicated in either cardioprotective or detrimental hypertrophic functions. Interestingly, ERK phosphorylated at threonine 188 and activated ERK5 (the big MAPK 1) are associated with pathological forms of hypertrophy. Finally, we examine the connection between ERK activation and hypertrophy in (i) transgenic mice overexpressing constitutively activated RTKs (receptor tyrosine kinases), (ii) animal models with mutated sarcomeric proteins characteristic of inherited hypertrophic cardiomyopathies (HCMs), and (iii) mice reproducing syndromic genetic RASopathies. Overall, the scientific literature suggests that during cardiac hypertrophy, ERK could be a \u201cgood\u201d player to be stimulated or a \u201cbad\u201d actor to be mitigated, depending on the pathophysiological context.<\/jats:p>","DOI":"10.3390\/ijms20092164","type":"journal-article","created":{"date-parts":[[2019,5,2]],"date-time":"2019-05-02T03:15:22Z","timestamp":1556766922000},"page":"2164","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":250,"title":["ERK: A Key Player in the Pathophysiology of Cardiac Hypertrophy"],"prefix":"10.3390","volume":"20","author":[{"given":"Simona","family":"Gallo","sequence":"first","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annapia","family":"Vitacolonna","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy"},{"name":"Department of Oncology, University of Turin, 10143 Orbassano (TO), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Bonzano","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Comoglio","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Crepaldi","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo (TO), Italy"},{"name":"Department of Oncology, University of Turin, 10143 Orbassano (TO), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1152\/physrev.1999.79.1.143","article-title":"Mitogen-Activated Protein Kinase: Conservation of a Three-Kinase Module from Yeast to Human","volume":"79","author":"Widmann","year":"1999","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.cell.2010.06.011","article-title":"Cell Signaling by Receptor Tyrosine Kinases","volume":"141","author":"Lemmon","year":"2010","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/s11248-006-9052-0","article-title":"In vivo functions of mitogen-activated protein kinases: conclusions from knock-in and knock-out mice","volume":"16","author":"Gerits","year":"2007","journal-title":"Transgenic. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6341","DOI":"10.1093\/emboj\/19.23.6341","article-title":"The MEK1-ERK1\/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice","volume":"19","author":"Bueno","year":"2000","journal-title":"EMBO J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1139\/o04-110","article-title":"Signaling through the extracellular signal-regulated kinase 1\/2 cascade in cardiac myocytes","volume":"82","author":"Clerk","year":"2004","journal-title":"Biochem. Cell. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.tcm.2003.11.002","article-title":"Stress-Activated MAP Kinases in Cardiac Remodeling and Heart Failure: New Insights from Transgenic Studies","volume":"14","author":"Petrich","year":"2004","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1161\/CIRCULATIONAHA.106.679589","article-title":"Mitogen-activated protein kinases in heart development and diseases","volume":"116","author":"Wang","year":"2007","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"938","DOI":"10.2119\/molmed.2011.00512","article-title":"Signaling to cardiac hypertrophy: Insights from human and mouse RASopathies","volume":"18","author":"Sala","year":"2012","journal-title":"Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1161\/CIRCULATIONAHA.110.942268","article-title":"Molecular Pathways Underlying Cardiac Remodeling During Pathophysiological Stimulation","volume":"122","author":"Kehat","year":"2010","journal-title":"Circulation"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1093\/emboj\/20.11.2757","article-title":"Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy","volume":"20","author":"Nicol","year":"2001","journal-title":"EMBO J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev.physiol.65.092101.142243","article-title":"Cardiac Hypertrophy: The Good, the Bad, and the Ugly","volume":"65","author":"Frey","year":"2003","journal-title":"Annu. Rev. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1056\/NEJMra072139","article-title":"Cardiac plasticity","volume":"358","author":"Hill","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1146\/annurev.physiol.62.1.289","article-title":"Genetic Dissection of Cardiac Growth Control Pathways","volume":"62","author":"MacLellan","year":"2000","journal-title":"Annu. Rev. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.cardiores.2004.04.031","article-title":"Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence","volume":"63","author":"Selvetella","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1067\/mhj.2001.113218","article-title":"Prognostic implications of left ventricular hypertrophy","volume":"141","author":"Vakili","year":"2001","journal-title":"Am. Heart. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/nrm3495","article-title":"Molecular basis of physiological heart growth: fundamental concepts and new players","volume":"14","author":"Maillet","year":"2013","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_17","first-page":"H2468","article-title":"ANG II receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice","volume":"266","author":"Rockman","year":"1994","journal-title":"Am. J. Physiol."},{"key":"ref_18","first-page":"H400","article-title":"Myosin heavy chain regulation and myocyte contractile depression after LV hypertrophy in aortic-banded mice","volume":"267","author":"Dorn","year":"1994","journal-title":"Am. J. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1111\/j.1440-1681.2009.05243.x","article-title":"Downregulation of survival signalling pathways and increased apoptosis in the transition of pressure overload-induced cardiac hypertrophy to heart failure","volume":"36","author":"Li","year":"2009","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1073\/pnas.041604898","article-title":"Activation and targeting of extracellular signal-regulated kinases by-arrestin scaffolds","volume":"98","author":"Luttrell","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7807","DOI":"10.1074\/jbc.C300443200","article-title":"Reciprocal regulation of angiotensin receptor-activated extracellular signal-regulated kinases by beta-arrestins 1 and 2","volume":"279","author":"Ahn","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1126\/science.1109237","article-title":"Transduction of Receptor Signals by beta-Arrestins","volume":"308","author":"Lefkowitz","year":"2005","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1074\/jbc.M506576200","article-title":"Beta-arrestin-dependent, G protein-independent ERK1\/2 activation by the beta2 adrenergic receptor","volume":"281","author":"Shenoy","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1016\/j.bbamem.2007.02.010","article-title":"Cardiac GPCRs: GPCR signaling in healthy and failing hearts","volume":"1768","author":"Salazar","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.cardiores.2005.12.015","article-title":"Integrin signalling: The tug-of-war in heart hypertrophy","volume":"70","author":"Brancaccio","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/S0165-6147(00)01679-5","article-title":"Cardiac mechanotransduction: from sensing to disease and treatment","volume":"22","author":"Tavi","year":"2001","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0955-0674(00)00190-3","article-title":"Expanding roles for \u03b2-arrestins as scaffolds and adapters in GPCR signaling and trafficking","volume":"13","author":"Miller","year":"2001","journal-title":"Curr. Opin. Cell. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1172\/JCI31901","article-title":"Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection","volume":"117","author":"Noma","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"14555","DOI":"10.1073\/pnas.0804745105","article-title":"Blockers alprenolol and carvedilol stimulate-arrestin-mediated EGFR transactivation","volume":"105","author":"Kim","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1161\/01.CIR.0000138190.50127.6A","article-title":"Raf-1 kinase is required for cardiac hypertrophy and cardiomyocyte survival in response to pressure overload","volume":"110","author":"Harris","year":"2004","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.ijcard.2018.05.068","article-title":"Extracellular signal-regulated kinase (ERK) activation preserves cardiac function in pressure overload induced hypertrophy","volume":"270","author":"Mutlak","year":"2018","journal-title":"Int. J. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14074","DOI":"10.1073\/pnas.0610906104","article-title":"Genetic inhibition of cardiac ERK1\/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo","volume":"104","author":"Purcell","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1146\/annurev.pharmtox.010909.105800","article-title":"Molecular mechanism of \u03b2-arrestin-biased agonism at seven-transmembrane receptors","volume":"52","author":"Reiter","year":"2012","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1172\/JCI200316100","article-title":"The alpha(1A\/C)- and alpha(1B)-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse","volume":"111","author":"Ishizaka","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Yeh, C.C., Fan, Y., Xu, Y., Yang, Y.L., Simpson, P.C., and Mann, M.J. (2017). Shift toward greater pathologic post-myocardial infarction remodeling with loss of the adaptive hypertrophic signaling of alpha1 adrenergic receptors in mice. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188471"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1253\/circj.CJ-08-0734","article-title":"Beta-arrestin-mediated signaling in the heart","volume":"72","author":"Patel","year":"2008","journal-title":"Circ. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1146\/annurev.cellbio.19.111401.091942","article-title":"Regulation of MAP Kinase Signaling Modules by Scaffold Proteins in Mammals","volume":"19","author":"Morrison","year":"2003","journal-title":"Annu. Rev. Cell. Dev. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/0092-8674(95)90206-6","article-title":"The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans","volume":"83","author":"Kornfeld","year":"1995","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.cellsig.2008.11.013","article-title":"Protein scaffolds in MAP kinase signalling","volume":"21","author":"Brown","year":"2009","journal-title":"Cell Signal"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"37","DOI":"10.3389\/fphar.2016.00037","article-title":"Scaffold proteins regulating extracellular regulated kinase function in cardiac hypertrophy and disease","volume":"7","author":"Liang","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1016\/j.ijcard.2012.04.093","article-title":"\u03b22-AR-induced Her2 transactivation mediated by Erbin confers protection from apoptosis in cardiomyocytes","volume":"167","author":"Shi","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5902","DOI":"10.1073\/pnas.1320350111","article-title":"Erbin is a negative modulator of cardiac hypertrophy","volume":"111","author":"Rachmin","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e1188241","DOI":"10.1080\/19420889.2016.1188241","article-title":"The function of Shoc2: A scaffold and beyond","volume":"9","author":"Jang","year":"2016","journal-title":"Commun. Integr. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1093\/cvr\/cvr103","article-title":"IQGAP1 regulates ERK1\/2 and AKT signalling in the heart and sustains functional remodelling upon pressure overload","volume":"91","author":"Carnevale","year":"2011","journal-title":"Cardiovasc. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3678","DOI":"10.4161\/cc.10.21.18202","article-title":"Morgana and melusin: Two fairies chaperoning signal transduction","volume":"10","author":"Ferretti","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nm805","article-title":"Melusin, a muscle-specific integrin \u03b21\u2013interacting protein, is required to prevent cardiac failure in response to chronic pressure overload","volume":"9","author":"Brancaccio","year":"2003","journal-title":"Nat. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1161\/01.RES.0000168028.36081.e0","article-title":"Cardiac Overexpression of melusin protects from dilated cardiomyopathy due to long-standing pressure overload","volume":"96","author":"Notte","year":"2005","journal-title":"Circ. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3870","DOI":"10.1172\/JCI34472","article-title":"An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice","volume":"118","author":"Sheikh","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Bang, M.L., Gu, Y., Dalton, N.D., Peterson, K.L., Chien, K.R., and Chen, J. (2014). The muscle ankyrin repeat proteins CARP, Ankrd2, and DARP are not essential for normal cardiac development and function at basal conditions and in response to pressure overload. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093638"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0378-1119(02)00924-1","article-title":"\u03b11-Adrenergic activation of the cardiac ankyrin repeat protein gene in cardiac myocytes","volume":"297","author":"Maeda","year":"2002","journal-title":"Gene"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1093\/cvr\/cvv108","article-title":"Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy","volume":"106","author":"Zhong","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/j.biopha.2016.08.016","article-title":"Icariin attenuated oxidative stress induced-cardiac apoptosis by mitochondria protection and ERK activation","volume":"83","author":"Song","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7460","DOI":"10.1128\/MCB.21.21.7460-7469.2001","article-title":"The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes","volume":"21","author":"Liang","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"6975","DOI":"10.1073\/pnas.0401833101","article-title":"Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity","volume":"101","author":"Aries","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"16484","DOI":"10.1074\/jbc.M010384200","article-title":"MAPK\/ERK overrides the apoptotic signaling from Fas, TNF, and TRAIL receptors","volume":"276","author":"Tran","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_56","first-page":"5988","article-title":"Inhibition of BAD phosphorylation either at serine 112 via extracellular signal-regulated protein kinase cascade or at serine 136 via Akt cascade sensitizes human ovarian cancer cells to cisplatin","volume":"60","author":"Hayakawa","year":"2000","journal-title":"Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"49511","DOI":"10.1074\/jbc.M208086200","article-title":"Nerve growth factor (NGF) down-regulates the Bcl-2 homology 3 (BH3) domain-only protein Bim and suppresses its proapoptotic activity by phosphorylation","volume":"277","author":"Biswas","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/ncb1005","article-title":"Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK","volume":"5","author":"Allan","year":"2003","journal-title":"Nat. Cell. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5301","DOI":"10.1038\/sj.onc.1207692","article-title":"MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells and at additional sites with cytotoxic okadaic acid or taxol","volume":"23","author":"Domina","year":"2004","journal-title":"Oncogene"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5151","DOI":"10.1093\/emboj\/cdf488","article-title":"IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation","volume":"21","author":"Garcia","year":"2002","journal-title":"EMBO J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"C82","DOI":"10.1152\/ajpcell.00287.2006","article-title":"Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system","volume":"292","author":"Mehta","year":"2007","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1161\/01.HYP.25.6.1252","article-title":"Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats","volume":"25","author":"Kim","year":"1995","journal-title":"Hypertens"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1161\/01.RES.73.3.439","article-title":"Rat angiotensin II (type 1A) receptor mRNA regulation and subtype expression in myocardial growth and hypertrophy","volume":"73","author":"Suzuki","year":"1993","journal-title":"Circ. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1073\/pnas.97.2.931","article-title":"Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling","volume":"97","author":"Paradis","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1161\/01.CIR.100.20.2093","article-title":"Angiotensin II type 1A receptor knockout mice display less left ventricular remodeling and improved survival after myocardial infarction","volume":"100","author":"Harada","year":"1999","journal-title":"Circulation"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1097\/00004872-200018090-00017","article-title":"Angiotensin II-induced cardiac hypertrophy is associated with different mitogen-activated protein kinase activation in normotensive and hypertensive mice","volume":"18","author":"Pellieux","year":"2000","journal-title":"J. Hypertens."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0002-9149(99)00259-3","article-title":"Role of the renin-angiotensin system in cardiac hypertrophy","volume":"83","author":"Yamazaki","year":"1999","journal-title":"Am. J. Cardiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1002\/jcp.25945","article-title":"HSF1 phosphorylation by ERK\/GSK3 suppresses RNF126 to sustain IGF-IIR expression for hypertension-induced cardiomyocyte hypertrophy","volume":"233","author":"Huang","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"3045","DOI":"10.1172\/JCI25330","article-title":"Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q\/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice","volume":"115","author":"Zhai","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1385\/CT:1:4:267","article-title":"Molecular mechanisms of cardiac hypertrophy induced by toxicants","volume":"1","author":"Chen","year":"2001","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1002\/jcp.25905","article-title":"Mitochondrial ROS-induced ERK1\/2 activation and HSF2-mediated AT1R upregulation are required for doxorubicin-induced cardiotoxicity","volume":"233","author":"Huang","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6841","DOI":"10.3892\/mmr.2015.4234","article-title":"Hydrogen sulfide attenuates doxorubicin-induced cardiotoxicity by inhibiting reactive oxygen species-activated extracellular signal-regulated kinase 1\/2 in H9c2 cardiac myocytes","volume":"12","author":"Liu","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.ejphar.2017.12.021","article-title":"A novel compound DT-010 protects against doxorubicin-induced cardiotoxicity in zebrafish and H9c2 cells by inhibiting reactive oxygen species-mediated apoptotic and autophagic pathways","volume":"820","author":"Tang","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.ejphar.2012.01.034","article-title":"Urotensin II prevents cardiomyocyte apoptosis induced by doxorubicin via Akt and ERK","volume":"680","author":"Chen","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.taap.2015.08.007","article-title":"Morphine preconditioning confers cardioprotection in doxorubicin-induced failing rat hearts via ERK\/GSK-3\u03b2 pathway independent of PI3K\/Akt","volume":"288","author":"He","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"H1925","DOI":"10.1152\/ajpheart.01054.2004","article-title":"Involvement of mitogen-activated protein kinases in adriamycin-induced cardiomyopathy","volume":"288","author":"Lou","year":"2005","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3727","DOI":"10.1111\/bph.13643","article-title":"Trastuzumab cardiotoxicity: from clinical trials to experimental studies","volume":"174","author":"Nemeth","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1056\/NEJMoa052306","article-title":"Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer","volume":"353","author":"Procter","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.echo.2014.01.014","article-title":"Doxorubicin and trastuzumab regimen induces biventricular failure in mice","volume":"27","author":"Milano","year":"2014","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/nm0502-459","article-title":"ErbB2 is essential in the prevention of dilated cardiomyopathy","volume":"8","author":"Crone","year":"2002","journal-title":"Nat. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/j.yjmcc.2003.09.012","article-title":"Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase\/Akt","volume":"35","author":"Fukazawa","year":"2003","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.tips.2015.03.005","article-title":"Anthracyclines\/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms","volume":"36","author":"Rochette","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1210\/rp.59.1.1","article-title":"Essential roles of Her2\/erbB2 in cardiac development and function","volume":"59","author":"Negro","year":"2004","journal-title":"Recent. Prog. Horm. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s12012-012-9183-x","article-title":"The dual-targeted HER1\/HER2 tyrosine kinase inhibitor lapatinib strongly potentiates the cardiac myocyte-damaging effects of doxorubicin","volume":"13","author":"Hasinoff","year":"2013","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1158\/1535-7163.MCT-15-0741","article-title":"Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes","volume":"15","author":"Mohan","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/nm.1893","article-title":"A new type of ERK1\/2 autophosphorylation causes cardiac hypertrophy","volume":"15","author":"Lorenz","year":"2009","journal-title":"Nat. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"7440","DOI":"10.1073\/pnas.1221999110","article-title":"Interference with ERK(Thr188) phosphorylation impairs pathological but not physiological cardiac hypertrophy","volume":"110","author":"Ruppert","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/cvr\/cvs249","article-title":"\u03b2-Adrenergic receptor stimulation causes cardiac hypertrophy via a G\u03b2\u03b3\/Erk-dependent pathway","volume":"96","author":"Vidal","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1039\/C6MB00255B","article-title":"Analyzing ERK 1\/2 signalling and targets","volume":"12","author":"Brietz","year":"2016","journal-title":"Mol. Biosyst."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1006\/bbrc.1995.2189","article-title":"Primary structure of BMK1: a new mammalian MAP Kinase","volume":"213","author":"Lee","year":"1995","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1161\/CIRCRESAHA.109.209320","article-title":"Targeted deletion of the extracellular signal-regulated protein kinase 5 attenuates hypertrophic response and promotes pressure overload-induced apoptosis in the heart","volume":"106","author":"Kimura","year":"2010","journal-title":"Circ. Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1113\/expphysiol.2006.036590","article-title":"Eccentric cardiac hypertrophy was induced by long-term intermittent hypoxia in rats","volume":"92","author":"Chen","year":"2007","journal-title":"Exp. Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1002\/jcb.22441","article-title":"Protein kinase C epsilon-dependent extracellular signal-regulated kinase 5 phosphorylation and nuclear translocation involved in cardiomyocyte hypertrophy with angiotensin II stimulation","volume":"109","author":"Zhao","year":"2009","journal-title":"J. Cell. Biochem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.febslet.2004.03.120","article-title":"Activation of big MAP kinase 1 (BMK1\/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion","volume":"566","author":"Cameron","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_95","first-page":"20732","article-title":"Effects of Wenyangzhenshuai Granule on ERK1\/2 and ERK5 activity in the myocardial tissue in a rabbit model of adriamycin-induced chronic heart failure","volume":"8","author":"Chen","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_96","first-page":"110","article-title":"Roles of FGF signals in heart development, health, and disease","volume":"4","author":"Itoh","year":"2016","journal-title":"Front. Cell. Dev. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1016\/j.bbadis.2013.08.008","article-title":"Met signaling in cardiomyocytes is required for normal cardiac function in adult mice","volume":"1832","author":"Arechederra","year":"2013","journal-title":"Biochim. Biophys. Acta Mol. Basis. Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1161\/HYPERTENSIONAHA.112.196543","article-title":"Loss of epidermal growth factor receptor in vascular smooth muscle cells and cardiomyocytes causes arterial hypotension and cardiac hypertrophy","volume":"61","author":"Schreier","year":"2013","journal-title":"Hypertension"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Sysa-Shah, P., Xu, Y., Guo, X., Belmonte, F., Kang, B., Bedja, D., Pin, S., Tsuchiya, N., and Gabrielson, K. (2012). Cardiac-specific over-expression of epidermal growth factor receptor 2 (ErbB2) induces pro-survival pathways and hypertrophic cardiomyopathy in mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042805"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Cilvik, S.N., Wang, J.I., Lavine, K.J., Uchida, K., Castro, A., Gierasch, C.M., Weinheimer, C.J., House, S.L., Kovacs, A., and Nichols, C.G. (2013). Fibroblast growth factor receptor 1 signaling in adult cardiomyocytes increases contractility and results in a hypertrophic cardiomyopathy. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082979"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.yjmcc.2016.02.017","article-title":"Cardiac concentric hypertrophy promoted by activated Met receptor is mitigated in vivo by inhibition of Erk1,2 signalling with Pimasertib","volume":"93","author":"Sala","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Leo, C., Sala, V., Morello, M., Chiribiri, A., Riess, I., Mancardi, D., Schiaffino, S., Ponzetto, C., and Crepaldi, T. (2011). Activated met signling in the developing mouse heart leads to cardiac disease. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0014675"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1161\/01.CIR.0000030181.63741.56","article-title":"Angiotensin II-induced cardiac hypertrophy and hypertension are attenuated by epidermal growth factor receptor antisense","volume":"106","author":"Kagiyama","year":"2002","journal-title":"Circulation"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1111\/jcmm.12763","article-title":"Novel EGFR inhibitors attenuate cardiac hypertrophy induced by angiotensin II","volume":"20","author":"Peng","year":"2016","journal-title":"J. Cell. Mol. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e00140","DOI":"10.1042\/BSR20130107","article-title":"Cardiac-targeting magnetic lipoplex delivery of SH-IGF1R plasmid attenuate norepinephrine-induced cardiac hypertrophy in murine heart","volume":"34","author":"Xu","year":"2014","journal-title":"Biosci. Rep."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.yjmcc.2017.10.001","article-title":"Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice","volume":"113","author":"Pires","year":"2017","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1253\/circj.CJ-14-0893","article-title":"Inherited cardiomyopathies","volume":"78","author":"Towbin","year":"2014","journal-title":"Circ. J."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/j.1540-8167.2007.00965.x","article-title":"Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics","volume":"19","author":"Alcalai","year":"2008","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1161\/CIRCULATIONAHA.106.174287","article-title":"Contemporary definitions and classification of the cardiomyopathies","volume":"113","author":"Maron","year":"2006","journal-title":"Circulation"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1161\/01.CIR.104.3.317","article-title":"Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy","volume":"104","author":"Patel","year":"2001","journal-title":"Circulation"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"10487","DOI":"10.1074\/jbc.RA118.002081","article-title":"Hypertrophic cardiomyopathy mutations increase myofilament Ca2+ buffering, alter intracellular Ca2+ handling, and stimulate Ca2+-dependent signaling","volume":"293","author":"Robinson","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/j.cell.2016.04.002","article-title":"A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy","volume":"165","author":"Davis","year":"2016","journal-title":"Cell"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e91225","DOI":"10.1172\/jci.insight.91225","article-title":"Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy","volume":"2","author":"Higgins","year":"2017","journal-title":"JCI Insight"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1161\/CIRCULATIONAHA.107.728865","article-title":"Deletion of Ptpn11 (Shp2) in cardiomyocytes causes dilated cardiomyopathy via effects on the extracellular signal-regulated kinase\/mitogen-activated protein kinase and RhoA signaling pathways","volume":"117","author":"Kontaridis","year":"2008","journal-title":"Circulation"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1038\/ng2073","article-title":"Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy","volume":"39","author":"Pandit","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/humu.21187","article-title":"Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation","volume":"31","author":"Kobayashi","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1172\/JCI44929","article-title":"MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1(L613V) mutation","volume":"121","author":"Wu","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Li, C., Chen, Z., Yang, H., Luo, F., Chen, L., Cai, H., Li, Y., You, G., Long, D., and Li, S. (2016). Selumetinib, an oral anti-neoplastic drug, may attenuate cardiac hypertrophy via targeting the ERK pathway. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0159079"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/9\/2164\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:48:34Z","timestamp":1760186914000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/9\/2164"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,1]]},"references-count":118,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["ijms20092164"],"URL":"https:\/\/doi.org\/10.3390\/ijms20092164","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,1]]}}}