Set7 deletion attenuates isoproterenol-induced cardiac fibrosis and delays cardiac dysfunction

Author:

Lunardon Guilherme1ORCID,de Oliveira Silva Tábatha1,Lino Caroline A.1,Lu Yao Wei2,Miranda Juliane B.1,Asprino Paula F.3,de Almeida Silva Amanda4,Nepomuceno Gabrielle T.5,Irigoyen Maria Cláudia Costa4,Carneiro-Ramos Marcela S.5,Takano Ana Paula C.1,Martinho Herculano da Silva5,Barreto-Chaves Maria Luiza M.1,Wang Da-Zhi26,Diniz Gabriela P.1ORCID

Affiliation:

1. 1Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil

2. 2Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, U.S.A.

3. 3Center for Molecular Oncology, Sírio-Libanês Hospital, Sao Paulo, Brazil

4. 4Department of Cardiopneumology, Heart Institute, Faculty of Medicine, University of Sao Paulo, Sao Paulo, Brazil

5. 5Center of Natural and Human Sciences, Federal University of ABC, Santo Andre, Brazil

6. 6Center for Regenerative Medicine, USF Health Heart Institute, University of South Florida, Tampa, FL, U.S.A.

Abstract

Abstract Cardiovascular diseases are the main cause of death worldwide. Recent studies have revealed the influence of histone-modifying enzymes in cardiac remodeling and heart dysfunction. The Set7 methyltransferase regulates the expression of several genes through the methylation of histones and modulates the activity of non-histone proteins. However, the role of Set7 in cardiac remodeling and heart dysfunction remains unknown. To address this question, wild-type (WT) and Set7 knockout (KO) male mice were injected with isoproterenol or saline. WT mice injected with isoproterenol displayed a decrease in Set7 activity in the heart. In addition, WT and Set7 KO mice injected with isoproterenol exhibited cardiac hypertrophy. Interestingly, Set7 deletion exacerbated cardiac hypertrophy in response to isoproterenol but attenuated myocardial fibrosis. Echocardiograms revealed that WT mice injected with isoproterenol had lowered ejection fractions and fractional shortening, and increased E′-wave deceleration time and E/A ratio compared with their controls. Conversely, Set7 KO mice did not show alteration in these parameters in response to isoproterenol. However, prolonged exposure to isoproterenol induced cardiac dysfunction both in WT and Set7 KO mice. Both isoproterenol and Set7 deletion changed the transcriptional profile of the heart. Moreover, Set7 deletion increased the expression of Pgc1α and mitochondrial DNA content in the heart, and reduced the expression of cellular senescence and inflammation markers in response to isoproterenol. Taken together, our data suggest that Set7 deletion attenuates isoproterenol-induced myocardial fibrosis and delays heart dysfunction, suggesting that Set7 plays an important role in cardiac remodeling and dysfunction in response to stress.

Publisher

Portland Press Ltd.

Subject

General Medicine

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