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

• Published in: Biology of sex differences Vol. 10; no. 1; p. 8
• Main Authors: Sanchez-Ruderisch, Hugo, Queirós, Ana Maria, Fliegner, Daniela, Eschen, Claudia, Kararigas, Georgios, Regitz-Zagrosek, Vera
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06.02.2019; BioMed Central; BMC
• Subjects: 17β-Estradiol; Animals; Aorta; Blood Pressure; Cardiac; Cardiovascular disease; Cell Line; Computer applications; Congestive heart failure; Dehydrogenases; ERβ; Estradiol; Estrogen Receptor beta - genetics; Estrogens; Experiments; Female; Females; Gender differences; Gene expression; Genetic regulation; Heart; Heart failure; Heart hypertrophy; Hormones; Hypertension; Hypertrophy; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - metabolism; Hypotheses; Male; Males; Metabolism; Mice, Inbred C57BL; Mice, Knockout; MicroRNA; MicroRNAs; MicroRNAs - metabolism; miRNA; Mitochondria; Mitochondrial; Mitochondrial Proteins - genetics; Mutation; Myocardium - metabolism; Phenols (Class of compounds); Pressure; Pressure overload; Protein turnover; Proteins; Risk factors; Sex Characteristics; Sex differences; Sex hormones; Steroid hormones; Ventricle; Pressure overload; Sex differences; microRNA; ERβ; Mitochondrial; Cardiac
• ISSN: 2042-6410; 2042-6410
• DOI: 10.1186/s13293-019-0222-1

Maladaptive 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. We employed the transverse aortic constriction model in mice and assessed the levels of five mitochondrial proteins, i.e., Auh, Crat, Decr1, Hadha, and Ndufs4. We 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. We 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.