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

• Published in: Cells (Basel, Switzerland) Switzerland), 2020-03, Vol.9 (4), p.833
• Main Authors: García, Raquel, Salido-Medina, Ana B, Gil, Aritz, Merino, David, Gómez, Jenny, Villar, Ana V, González-Vílchez, Francisco, Hurlé, María A, Nistal, J Francisco
• Format: Article
• Language: English
• Subjects: Animals; Aortic stenosis; aortic stenosis patients; Aortic valve; Aortic Valve Stenosis - blood; Aortic Valve Stenosis - diagnostic imaging; Aortic Valve Stenosis - genetics; Aortic Valve Stenosis - physiopathology; Biopsy; cardiac remodeling; Cardiovascular disease; Case-Control Studies; Collagen; Electrocardiography; Female; Females; Fibroblasts; Fibroblasts - metabolism; Fibrosis; Flow velocity; Gender differences; Gene expression; Gene Expression Regulation; Gonads - metabolism; Heart; Heart Ventricles - pathology; Hormones - metabolism; Humans; Hypertrophy; Immunoassay; Laboratory animals; Linear Models; Liver; Male; Males; Mice, Inbred C57BL; MicroRNAs - blood; MicroRNAs - genetics; MicroRNAs - metabolism; miR-29b; Myocardium; Myocardium - metabolism; Myocardium - pathology; Organ Size; Pressure; pressure overload; Sex; Sex Characteristics; sex differences; Sexual dimorphism; Stenosis; Structure-function relationships; Studies; Surgery; Transforming Growth Factor beta - metabolism; Ultrasonic imaging; Vascular Remodeling - genetics; Ventricle
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9040833

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.