Unraveling the Impact of miR-146a in Pulmonary Arterial Hypertension Pathophysiology and Right Ventricular Function
Résumé
Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by excessive pulmonary vascular remodeling, leading to elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. MicroRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both hallmarks of PAH. This study aimed to investigate the effects of miR-146a through pharmacological or genetic inhibition on experimental PAH and RV pressure overload animal models. Additionally, we examined the overexpression of miR-146a on human pulmonary artery smooth muscle cells (hPASMCs). Here, we showed that miR-146a genic expression was increased in the lungs of patients with PAH and the plasma of monocrotaline (MCT) rats. Interestingly, genetic ablation of miR-146a improved RV hypertrophy and systolic pressures in Sugen 5415/hypoxia (SuHx) and pulmonary arterial banding (PAB) mice. Pharmacological inhibition of miR-146a improved RV remodeling in PAB-wild type mice and MCT rats, and enhanced exercise capacity in MCT rats. However, overexpression of miR-146a did not affect proliferation, migration, and apoptosis in control-hPASMCs. Our findings show that miR-146a may play a significant role in RV function and remodeling, representing a promising therapeutic target for RV hypertrophy and, consequently, PAH.
Mots clés
Humans
Male
Animals
Disease Models
Animal
Mice
Rats
*MicroRNAs/genetics/metabolism
Sprague-Dawley
*Pulmonary Arterial Hypertension/genetics/metabolism
*Pulmonary Artery/metabolism/pathology
*Ventricular Function
Right
Cell Proliferation/genetics
Hypertension
Pulmonary/genetics/metabolism/physiopathology
Hypertrophy
Right Ventricular/genetics/physiopathology/metabolism
miR-146a
Monocrotaline
Myocytes
Smooth Muscle/metabolism
pulmonary arterial hypertension (PAH)
right ventricular (RV) failure
right ventricular (RV) hypertrophy
Vascular Remodeling/genetics