Sex-specific regulation of cardiac microRNAs targeting mitochondrial proteins in pressure overload

Abstract

BackgroundMaladaptive remodeling in pressure overload (PO)-induced left ventricular hypertrophy (LVH) may lead to heart failure. Major sex differences have been reported in this process. The steroid hormone 17β-estradiol, along with its receptors ERα and ERβ, is thought to be crucial for sex differences and is expected to be protective, but this may not hold true for males. Increasing evidence demonstrates a major role for microRNAs (miRNAs) in PO-induced LVH. However, little is known about the effects of biological sex and ERβ on cardiac miRNA regulation and downstream mitochondrial targets. We aimed at the analysis of proteins involved in mitochondrial metabolism testing the hypothesis that they are the target of sex-specific miRNA regulation.MethodsWe employed the transverse aortic constriction model in mice and assessed the levels of five mitochondrial proteins, i.e., Auh, Crat, Decr1, Hadha, and Ndufs4.ResultsWe found a significant decrease of the mitochondrial proteins primarily in the male overloaded heart compared with the corresponding control group. Following computational analysis to identify miRNAs putatively targeting these proteins, our in vitro experiments employing miRNA mimics demonstrated the presence of functional target sites for miRNAs in the 3′-untranslated region of the messenger RNAs coding for these proteins. Next, we assessed the levels of the functionally validated miRNAs under PO and found that their expression was induced only in the male overloaded heart. In contrast, there was no significant effect on miRNA expression in male mice with deficient ERβ.ConclusionWe put forward that the male-specific induction of miRNAs and corresponding downregulation of downstream protein targets involved in mitochondrial metabolism may contribute to sex-specific remodeling in PO-induced LVH.

The Zebrafish (Danio rerio) Is a Relevant Model for Studying Sex-Specific Effects of 17β-Estradiol in the Adult Heart

“…The steroid hormone 17β-estradiol (E2) is thought to be one of the major factors associated with age-specific cardiac remodeling [4], as well as for mediating sex-specific effects in the heart. Along this line, we previously reported direct effects of E2 in the mouse heart [5][6][7][8] and also E2-mediated cardiac effects that may differ significantly between the sexes [9][10][11][12][13]. Although E2 is believed to be cardioprotective in females, it may exert deleterious effects in males [10,14].…”

Assessment of Bones Deficient in Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences

“…Protein lysates were isolated from tibiae as described previously [32,33,34]. Independent biological replicates for each group were run separately on SDS-PAGE gels and transferred to nitrocellulose membranes using standard procedures.…”

Approaching Sex Differences in Cardiovascular Non-Coding RNA Research

“…The steroid hormone 17-β-estradiol and its receptors ERα and ERβ play important role in the development of sex differences in CVD [ 123 ]. Recent findings have demonstrated that ERβ may contribute to significantly altered expression of cardiac miRNA, for instance downregulation of miR-143 [ 123 ].…”

“…The steroid hormone 17-β-estradiol and its receptors ERα and ERβ play important role in the development of sex differences in CVD [ 123 ]. Recent findings have demonstrated that ERβ may contribute to significantly altered expression of cardiac miRNA, for instance downregulation of miR-143 [ 123 ]. A widely expressed miR-181a regulates ERα in female cortical astrocytes and demonstrated protective effect against cerebral artery occlusion in female mice [ 124 ].…”