Abstract
Recent studies have revealed the influence of histone-modifying enzymes in cardiac remodeling and dysfunction. The Set7 methyltransferase regulates the expression of several genes through methylation of histones and modulates the activity of non-histone proteins. However, the role of Set7 in heart dysfunction remains unknown. To answer this question, wild type (WT) and Set7 knockout (KO) male mice were injected with isoproterenol (iso) or saline (s) subcutaneously for 14 days. The WTiso mice displayed decreased Set7 activity in the heart compared to WTs mice (Table 1). Both WTiso and KOiso mice exhibited increased heart weight to tibia length ratio (HW/TL) and cardiomyocyte area. However, KOiso mice had higher HW/TL and cardiomyocyte area compared to WTiso mice. Sirius Red staining revealed that both WT and KO mice injected with iso had increased myocardial fibrosis compared to their controls. Nonetheless, loss of Set7 attenuated iso-induced myocardial fibrosis. Echocardiogram showed that WTiso mice had lower ejection fraction (EF) and fractional shortening (FS), and higher E/A ratio compared to WTs mice. Conversely, KOiso mice did not show alteration on these parameters compared to their controls. RNA sequencing analysis revealed that biological processes related to oxidant detoxication, cellular respiration, and anti-inflammatory response were enriched in the heart of KOiso mice compared to WTiso mice. On the other hand, biological processes related to cell aging, interferon production, and immune response were downregulated in the heart of KOiso mice compared to WTiso mice. Collectively, our data suggest that Set7 deletion prevents iso-induced heart dysfunction.
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