Endothelial dysfunction is a key player in advancing vascular pathology in pulmonary arterial hypertension (PAH), a disease essentially characterized by intense remodeling of the pulmonary vasculature, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, and thrombosis in situ. These vascular features culminate in an increase in pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past years, there has been a great development in our understanding of pulmonary endothelial biology related to the genetic and molecular mechanisms that modulate the endothelial response to direct or indirect injury and how their dysregulation can promote PAH pathogenesis. Ion channels are key regulators of vasoconstriction and proliferative/apoptotic phenotypes; however, they are poorly studied at the endothelial level. The current review will describe and categorize different expression, functions, regulation, and remodeling of endothelial ion channels (K⁺, Ca²⁺, Na⁺, and Cl⁻ channels) in PAH. We will focus on the potential pathogenic role of ion channel deregulation in the onset and progression of endothelial dysfunction during the development of PAH and its potential therapeutic role.

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.

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.