Cardiomyocyte-specific overexpression of oestrogen receptor improves survival and cardiac function after myocardial infarction in female and male mice

I., Schuster, S., Mahmoodzadeh, E., Dworatzek, F., Jaisser, S., Messaoudi, I., Morano, V., Regitz-Zagrosek

Clinical Science |

BACKGROUND: Estrogen receptor beta (ERβ) activation has been shown to be cardioprotective, but the involved cell types and mechanisms are not understood. To investigate whether ERβ restricted to cardiomyocytes contributes to observed cardioprotection, we tested the effects of a cardiomyocyte-specific ERβ overexpression (ERβ-OE) on survival, cardiac remodelling and function after myocardial infarction (MI) and studied potentially involved molecular pathways.\n\nMETHODS AND RESULTS: Female and male mice with cardiomyocyte-specific ERβ-OE and wild type (WT) littermates were subjected to chronic anterior coronary artery ligation or sham surgery. Two weeks after MI, ERβ-OE mice showed improved survival (100 and 83% vs 76 and 58% in WT females and males respectively). ERβ-OE was associated with attenuated left ventricular (LV) dilatation, smaller increase in heart weight, less lung congestion at similar MI size, and improved systolic and diastolic function in both sexes. We identified two potential pathways for ERβ mediated myocardial protection. First, male and female ERβ-OE mice had a lower reduction of SERCA2a expression after MI, suggesting less reduction in diastolic Ca2+-reuptake into sarcoplasmic reticulum post MI. Second, male ERβ-OE revealed attenuated cardiac fibrosis in the remote LV tissue and expression of fibrosis markers Col I, Col III, periostin, and miR21.\n\nCONCLUSIONS: Cardiomyocyte-specific ERβ-OE improved survival associated with reduced maladaptive remodelling, improved cardiac function and less heart failure development after MI in both sexes. These effects seem to be related, at least in part, to a better maintenance of Ca2+-cycling in both sexes and a lower induction of cardiac fibrosis in males after MI.