Pulmonary arterial hypertension (PAH), is a chronic disorder characterized by excessive pulmonary vascular remodelling, resulting in elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. PAH remains incurable, and new therapeutic approaches are required. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both important hallmarks of PAH.

This study aims to investigate miR-146a role in the pathophysiology of PAH and RV failure.

Sprague Dawley rats received a subcutaneous injection of monocrotaline (MCT group) or vehicle (CTL group) and, after fourteen days they were treated, by nebulization, with an anti-miR-146a, forming four distinct groups: CTL-treated; CTL-untreated, MCT-treated, and MCT-untreated. Twenty-seven days after MCT injection, echocardiographic and invasive hemodynamic evaluations were performed in all animal groups. Also, wild-type (WT) and miR-146a knock-out (KO) mice were submitted to either 3 weeks of chronic hypoxia-induced PAH with weekly Sugen 5416 administration (SuHx).

Compared to MCT-untreated rats, the MCT-treated rats showed decreased RV hypertrophy, decreased RV end-diastolic diameter/left ventricle end-diastolic diameter (RVEDD/LVEDD) ratio, and decreased in RV diastolic pressures. KO-SuHx group, when compared to WT-SuHx group, showed decreased RV hypertrophy and decreased RV systolic pressures and dilation, as well as lower RV end-diastolic diameter (RVEDDi) and right atria area (RAAi).

Our findings show that miR-146a pharmacological or genetic inhibition reduces RV remodelling and improves cardiac function. Thus, miR-146a represents a promising therapeutic target in PAH.