Sex-Specific Regulation of miR-29b in the Myocardium Under Pressure Overload is Associated with Differential Molecular, Structural and Functional Remodeling Patterns in Mice and Patients with Aortic Stenosis

Abstract

Pressure overload in patients with aortic stenosis (AS) induces an adverse remodeling of the left ventricle (LV) in a sex-specific manner. We assessed whether a sex-specific miR-29b dysregulation underlies this sex-biased remodeling pattern, as has been described in liver fibrosis. We studied mice with transverse aortic constriction (TAC) and patients with AS. miR-29b was determined in the LV (mice, patients) and plasma (patients). Expression of remodeling-related markers and histological fibrosis were determined in mouse LV. Echocardiographic morpho-functional parameters were evaluated at baseline and post-TAC in mice, and preoperatively and 1 year after aortic valve replacement (AVR) in patients with AS. In mice, miR-29b LV regulation was opposite in TAC-males (down-regulation) and TAC-females (up-regulation). The subsequent changes in miR-29b targets (collagens and GSK-3β) revealed a remodeling pattern that was more fibrotic in males but more hypertrophic in females. Both systolic and diastolic cardiac functions deteriorated more in TAC-females, thus suggesting a detrimental role of miR-29b in females, but was protective in the LV under pressure overload in males. Clinically, miR-29b in controls and patients with AS reproduced most of the sexually dimorphic features observed in mice. In women with AS, the preoperative plasma expression of miR-29b paralleled the severity of hypertrophy and was a significant negative predictor of reverse remodeling after AVR; therefore, it may have potential value as a prognostic biomarker.

LncRNA TUG1 Regulates Proliferation of Cardiac Fibroblast via the miR-29b-3p/TGF-β1 Axis

“…According to these data, we concluded that TUG1 regulates the proliferation of CFs via targeting miR-29b-3p. Consistently, in a study of aortic stenosis (AS), downregulation of miR-29b-3p in fibroblasts is considered to be the mechanism underlying the fibrotic effect of TGF-β in the stressed left ventricle myocardium (32). These findings supported our speculation about the crucial role of TUG1/miR-29b-3p in myocardial fibrosis, even in the progression of paroxysmal AF to persistent and permanent AF.…”

Sex-Specific Features of Calcific Aortic Valve Disease

“…Besides, a sex-specific microRNA-29b (miR-29b) dysregulation was observed in mice subjected to TAC, pointing out a sex-influenced left ventricle remodeling pattern [ 81 ]. This study provided the evidence demonstrating that sex differences in left ventricular remodeling (molecular, structural, and morpho-functional) involve sex-specific regulation of miR-29b in mice with TAC and under the clinical AS conditions.…”

Role of Biological Sex in the Cardiovascular-Gut Microbiome Axis

“…Women are also more likely to present with HF with preserved ejection fraction (81,82), which may be due to sex-biased remodeling of myocardial extracellular matrix (83), and the decline of estrogen at menopause might contribute to its pathogenesis (84). Along this line, under pressure overload, there is a higher proportion of male patients with increased left ventricular mass and enddiastolic diameter, and decreased left ventricular relative wall thickness and function (85)(86)(87)(88)(89)(90)(91), associated with greater activation of inflammatory factors (92,93). Physiological differences between men and women may also lead to sex differences in the response to treatment (2,(94)(95)(96)(97).…”