MiR-199a family members are differentially regulated during physiological and pathological cardiac hypertrophy

Among potential molecular mechanisms supporting cardiovascular homeostasis, miRNAs (miRs) represent interesting candidates. We recently highlighted that miR-199a controls the Nitric oxide synthase/nitric oxide (NOS/NO) pathway in the endothelium and showed that both mature strands of miR-199a are overexpressed in heart and vessels from a mouse model of hypertension. Here, we investigated the fate of miR-199a in heart and vessels from mice developing physiological or pathological cardiac hypertrophy. Our working hypothesis is that alterations in cell phenotypes driven by changes in miR-199a abundance account for cardiac and/or vascular adaptation to increased workload in patho-physiological contexts. C57BL/6J mice were subjected to either voluntary dynamic wheel training for 22 weeks or underwent transverse aortic constriction (TAC) surgery, resulting in physiological and pathological cardiac hypertrophy, respectively. An opposite modulation of miR-199a-3p and miR-199a-5p expression was observed in vessels and heart from running vs TAC mice, correlating with opposite regulation of Retinobastoma1 (RB1) in cardiac tissue. The authors found that miR-199a-3p upregulation, by indirectly modulating CCAAT/enhancer binding protein (C/EBP)β, promotes cardiomyocyte hypertrophy in pathological settings, while its repression by exercise drives metabolic adaptations associated with physiological remodeling. Interestingly, miR-199a-5p repression also directly targets Sirtuin 1 (Sirt-1) and Peroxisome proliferator-activated receptor coactivator (PGC1)α. Taken together, The authors' findings indicate that both mature arms of miR-199a act in tandem to drive morphologic and metabolic adaptations encountered in physiological and pathological cardiac hypertrophy.