{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:42:40Z","timestamp":1785213760069,"version":"3.55.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"2","funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["320030_147121\/1"],"award-info":[{"award-number":["320030_147121\/1"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Clinical studies suggest beneficial effects of renin\u2013angiotensin system blockade for prevention of left ventricular (LV) dysfunction after chemotherapy. However, the efficacy of this strategy as primary prevention has been poorly studied. This study aimed at identifying the pathophysiological mechanisms by which mineralocorticoid receptor antagonism (MRA) or angiotensin converting enzyme inhibition (ACEi) provide protection against doxorubicin-induced cardiotoxicity (DIC) in mouse models of acute and chronic toxicity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Acute DIC was induced by a single injection of Dox at 15\u2009mg\/kg and chronic DIC applied 5 injections of Dox at 4\u2009mg\/kg\/week. MRA was achieved using eplerenone or cardiomyocyte-specific ablation of the MR gene in transgenic mice and ACEi using enalapril. Drugs were provided with the first dose of Dox and applied until the end of the study. In both model of DIC, Dox induced cardiac atrophy with decreased LV volume, reduced cardiomyocyte cell size, and cardiac dysfunction. In the acute model, neither MRA nor ACEi protected against these manifestations of DIC. In the chronic model, concomitant treatment with eplerenone did not protect against DIC and drastically increased plasma aldosterone levels and cardiac levels of angiotensin II type 1 receptor and of connective tissue growth factor (CTGF), as observed in acute DIC. Enalapril treatment in the chronic model, however, protected against cardiac dysfunction and cardiomyocyte atrophy and was associated with increased activation of the PI3K\/AKT\/mTOR pathway along with normal levels of CTGF.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Enalapril and eplerenone disparately impact on cellular signalling in DIC. Eplerenone, on top of Dox treatment was not protective and associated with increased levels of plasma aldosterone and of cardiac CTGF. In contrast, we show that primary prevention with enalapril preserves LV morphology and function in a clinically relevant model of chronic DIC, with increased stimulation of the PI3K\/AKT\/mTOR axis and normal CTGF levels suggesting potential therapeutic implications.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvx162","type":"journal-article","created":{"date-parts":[[2017,8,10]],"date-time":"2017-08-10T07:10:28Z","timestamp":1502349028000},"page":"272-281","source":"Crossref","is-referenced-by-count":73,"title":["Diverging effects of enalapril or eplerenone in primary prevention against doxorubicin-induced cardiotoxicity"],"prefix":"10.1093","volume":"114","author":[{"given":"Roger","family":"Hullin","sequence":"first","affiliation":[{"name":"Service of Cardiology, Cardiovascular Department, Lausanne University Hospital (CHUV) Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie","family":"M\u00e9trich","sequence":"additional","affiliation":[{"name":"Service of Cardiology, Cardiovascular Department, Lausanne University Hospital (CHUV) Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Sarre","sequence":"additional","affiliation":[{"name":"Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Basquin","sequence":"additional","affiliation":[{"name":"Service of Cardiology, Cardiovascular Department, Lausanne University Hospital (CHUV) Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Maillard","sequence":"additional","affiliation":[{"name":"Service of Nephrology, Medicine Department, Lausanne University Hospital (CHUV), Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Regamey","sequence":"additional","affiliation":[{"name":"Service of Cardiology, Cardiovascular Department, Lausanne University Hospital (CHUV) Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Martin","sequence":"additional","affiliation":[{"name":"Service of Cardiology, Cardiovascular Department, Lausanne University Hospital (CHUV) Lausanne, Switzerland;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,9,7]]},"reference":[{"key":"2019090908282562600_cvx162-B1","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1016\/j.amjcard.2013.08.026","article-title":"Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity","volume":"112","author":"Lotrionte","year":"2013","journal-title":"Am J Cardiol"},{"key":"2019090908282562600_cvx162-B2","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/med.21280","article-title":"Doxorubicin-induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy","volume":"34","author":"Carvalho","year":"2014","journal-title":"Med Res Rev"},{"key":"2019090908282562600_cvx162-B3","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1210\/endo-127-3-1495","article-title":"Adriamycin-induced increase in serum aldosterone levels: effects in riboflavin-sufficient and riboflavin-deficient rats","volume":"127","author":"Pinto","year":"1990","journal-title":"Endocrinology"},{"key":"2019090908282562600_cvx162-B4","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1136\/postgradmedj-2015-133535","article-title":"Cardioprotective role of beta-blockers and angiotensin antagonists in early-onset anthracyclines-induced cardiotoxicity in adult patients: a systematic review and meta-analysis","volume":"91","author":"Yun","year":"2015","journal-title":"Postgrad Med J"},{"key":"2019090908282562600_cvx162-B5","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/ejhf.196","article-title":"Protective effects of spironolactone against anthracycline-induced cardiomyopathy","volume":"17","author":"Akpek","year":"2015","journal-title":"Eur J Heart Fail"},{"key":"2019090908282562600_cvx162-B6","doi-asserted-by":"crossref","first-page":"4517","DOI":"10.1200\/JCO.2002.12.102","article-title":"Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer","volume":"20","author":"Lipshultz","year":"2002","journal-title":"J Clin Oncol"},{"key":"2019090908282562600_cvx162-B7","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1161\/CIRCULATIONAHA.114.013777","article-title":"Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy","volume":"131","author":"Cardinale","year":"2015","journal-title":"Circulation"},{"key":"2019090908282562600_cvx162-B8","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1093\/cvr\/cvx078","article-title":"Inhibition of the cardiac myocyte mineralocorticoid receptor ameliorates doxorubicin-induced cardiotoxicity","volume":"114","author":"Lother","year":"2018","journal-title":"Cardiovasc Res"},{"key":"2019090908282562600_cvx162-B9","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1093\/eurheartj\/ehl013","article-title":"Tissue Doppler imaging predicts left ventricular dysfunction and mortality in a murine model of cardiac injury","volume":"27","author":"Neilan","year":"2006","journal-title":"Eur Heart J"},{"key":"2019090908282562600_cvx162-B10","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1210\/en.2005-0860","article-title":"Development of a panel of monoclonal antibodies against the mineralocorticoid receptor","volume":"147","author":"Gomez-Sanchez","year":"2006","journal-title":"Endocrinology"},{"key":"2019090908282562600_cvx162-B11","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.regpep.2009.12.002","article-title":"Role of Rho kinase and oxidative stress in cardiac fibrosis induced by aldosterone and salt in angiotensin type 1a receptor knockout mice","volume":"160","author":"Kagiyama","year":"2010","journal-title":"Regul Pept"},{"key":"2019090908282562600_cvx162-B12","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1161\/01.CIR.0000153800.09920.40","article-title":"Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload","volume":"111","author":"Kuster","year":"2005","journal-title":"Circulation"},{"key":"2019090908282562600_cvx162-B13","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1161\/CIRCULATIONAHA.106.653964","article-title":"Complementary and incremental mortality risk prediction by cortisol and aldosterone in chronic heart failure","volume":"115","author":"Guder","year":"2007","journal-title":"Circulation"},{"key":"2019090908282562600_cvx162-B14","doi-asserted-by":"crossref","first-page":"180.","DOI":"10.1186\/1479-5876-9-180","article-title":"The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism","volume":"9","author":"Eudy","year":"2011","journal-title":"J Transl Med"},{"key":"2019090908282562600_cvx162-B15","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.mayocp.2014.05.013","article-title":"Evaluation and management of patients with heart disease and cancer: cardio-oncology","volume":"89","author":"Herrmann","year":"2014","journal-title":"Mayo Clin Proc"},{"key":"2019090908282562600_cvx162-B16","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1093\/cvr\/cvs282","article-title":"Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes","volume":"96","author":"Kawaguchi","year":"2012","journal-title":"Cardiovasc Res"},{"key":"2019090908282562600_cvx162-B17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1093\/cvr\/cvw032","article-title":"Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity","volume":"110","author":"Zhan","year":"2016","journal-title":"Cardiovasc Res"},{"key":"2019090908282562600_cvx162-B18","doi-asserted-by":"crossref","first-page":"9287","DOI":"10.1158\/0008-5472.CAN-10-2664","article-title":"Nox2 NADPH oxidase promotes pathologic cardiac remodeling associated with Doxorubicin chemotherapy","volume":"70","author":"Zhao","year":"2010","journal-title":"Cancer Res"},{"key":"2019090908282562600_cvx162-B19","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1161\/CIRCULATIONAHA.108.799700","article-title":"Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mammalian target of rapamycin pathway","volume":"119","author":"Zhu","year":"2009","journal-title":"Circulation"},{"key":"2019090908282562600_cvx162-B20","doi-asserted-by":"crossref","first-page":"H1466","DOI":"10.1152\/ajpheart.00795.2008","article-title":"Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro","volume":"296","author":"Mukhopadhyay","year":"2009","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2019090908282562600_cvx162-B21","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1161\/01.CIR.0000048192.52098.DD","article-title":"Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction","volume":"107","author":"Pacher","year":"2003","journal-title":"Circulation"},{"key":"2019090908282562600_cvx162-B22","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.steroids.2014.08.013","article-title":"Cardiac effects of aldosterone: does gender matter?","volume":"91","author":"Mihailidou","year":"2014","journal-title":"Steroids"},{"key":"2019090908282562600_cvx162-B23","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1161\/01.HYP.0000025146.19104.FE","article-title":"Efficacy of eplerenone added to renin\u2013angiotensin blockade in hypertensive patients","volume":"40","author":"Krum","year":"2002","journal-title":"Hypertension"},{"key":"2019090908282562600_cvx162-B24","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.steroids.2014.05.017","article-title":"Mineralocorticoid receptor signaling: crosstalk with membrane receptors and other modulators","volume":"91","author":"Meinel","year":"2014","journal-title":"Steroids"},{"key":"2019090908282562600_cvx162-B25","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1161\/CIRCRESAHA.116.305381","article-title":"Getting to the heart of the matter: new insights into cardiac fibrosis","volume":"116","author":"Leask","year":"2015","journal-title":"Circ Res"},{"key":"2019090908282562600_cvx162-B26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12079-009-0071-5","article-title":"Connective tissue growth factor (CCN2, CTGF) and organ fibrosis: lessons from transgenic animals","volume":"4","author":"Brigstock","year":"2010","journal-title":"J Cell Commun Signal"},{"key":"2019090908282562600_cvx162-B27","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1161\/HYPERTENSIONAHA.112.198986","article-title":"Aldosterone-specific activation of cardiomyocyte mineralocorticoid receptor in vivo","volume":"61","author":"Messaoudi","year":"2013","journal-title":"Hypertension"},{"key":"2019090908282562600_cvx162-B28","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1161\/HYPERTENSIONAHA.110.163287","article-title":"Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function","volume":"57","author":"Lother","year":"2011","journal-title":"Hypertension"},{"key":"2019090908282562600_cvx162-B29","doi-asserted-by":"crossref","first-page":"18.","DOI":"10.1186\/s12947-015-0011-x","article-title":"The role of renin angiotensin system antagonists in the prevention of doxorubicin and trastuzumab induced cardiotoxicity","volume":"13","author":"Akolkar","year":"2015","journal-title":"Cardiovasc Ultrasound"},{"key":"2019090908282562600_cvx162-B30","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.jtcvs.2010.07.097","article-title":"Pretreatment with angiotensin-converting enzyme inhibitor improves doxorubicin-induced cardiomyopathy via preservation of mitochondrial function","volume":"142","author":"Hiona","year":"2011","journal-title":"J Thorac Cardiovasc Surg"},{"key":"2019090908282562600_cvx162-B31","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1016\/j.bbamcr.2016.01.003","article-title":"mTOR, cardiomyocytes and inflammation in cardiac hypertrophy","volume":"1863","author":"Xu","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"2019090908282562600_cvx162-B32","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1161\/01.CIR.0000057979.36322.88","article-title":"Rapamycin attenuates load-induced cardiac hypertrophy in mice","volume":"107","author":"Shioi","year":"2003","journal-title":"Circulation"},{"key":"2019090908282562600_cvx162-B33","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1634\/theoncologist.2013-0355","article-title":"Treatment-related mortality with everolimus in cancer patients","volume":"19","author":"Wesolowski","year":"2014","journal-title":"Oncologist"}],"container-title":["Cardiovascular Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cardiovascres\/article-pdf\/114\/2\/272\/29815548\/cvx162.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,20]],"date-time":"2019-09-20T03:47:50Z","timestamp":1568951270000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article\/114\/2\/272\/4107344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,7]]},"references-count":33,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,9,7]]},"published-print":{"date-parts":[[2018,2,1]]}},"URL":"https:\/\/doi.org\/10.1093\/cvr\/cvx162","relation":{},"ISSN":["0008-6363","1755-3245"],"issn-type":[{"value":"0008-6363","type":"print"},{"value":"1755-3245","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,2,1]]},"published":{"date-parts":[[2017,9,7]]}}}