MicroRNA-21 regulates right ventricular remodeling secondary to pulmonary arterial pressure overload

Right ventricular (RV) function is a critical determinant of survival in patients with pulmonary arterial hypertension (PAH). While miR-21 is known to associate with vascular remodeling in small animal models of PAH, its role in RV remodeling in large animal models has not been characterized. Herein, we investigated the role of miR-21 in RV dysfunction using a sheep model of PAH secondary to pulmonary arterial constriction (PAC). RV structural and functional remodeling were examined using ultrasound imaging. Our results showed that post PAC, RV strain significantly decreased at the basal region compared with t the control. Moreover, such dysfunction was accompanied by increases in miR-21 levels. To determine the role of miR-21 in RV remodeling secondary to PAC, we investigated the molecular alteration secondary to phenylephrine induced hypertrophy and miR21 overexpression in vitro using neonatal rat ventricular myocytes (NRVMs). We found that overexpression of miR-21 in the setting of hypertrophic stimulation augmented only the expression of proteins critical for mitosis but not cytokinesis. Strikingly, this molecular alteration was associated with an eccentric cellular hypertrophic phenotype similar to what we observed in vivo PAC animal model in sheep. Importantly, this hypertrophic change was diminished upon suppressing miR-21 in NRVMs. Collectively, our in vitro and in vivo data demonstrate that miR-21 is a critical contributor in the development of RV dysfunction and could represent a novel therapeutic target for PAH associated RV dysfunction. Summary of miR-21 related cardiac hypertrophy under pressure overload. Illustration of pressure overload-induced functional decline at the basal region of RV through miR-21 regulated increases in mitosis but incomplete cytokinesis. [Display omitted] •Post pulmonary arterial pressure overload, the declined RV function at basal region correlates with miR-21 expression.•miR-21 is critical in mitosis, incomplete cytokinesis and elongation of RV cardiomyocytes facing RV pressure overload.•Our results reveal the potential of miR-21 as a thrapeutic target for the treatment of RV dysfunction secondary to PAH.