Cardiovascular R&D Centre-UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
Paris-Porto Pulmonary Hypertension Collaborative Laboratory (3PH), UMR_S 999, INSERM, Université Paris-Saclay, 91190 Paris, France.
Int J Mol Sci. 2024 Jul 24;25(15):8054. doi: 10.3390/ijms25158054.
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.
肺动脉高压（PAH）是一种慢性疾病，其特征为肺血管过度重塑，导致肺血管阻力升高以及右心室（RV）负荷过重和衰竭。微小 RNA-146a（miR-146a）促进血管平滑肌细胞增殖和血管新生内膜增生，这两者都是 PAH 的特征。本研究旨在通过药理学或遗传学抑制 miR-146a 对实验性 PAH 和 RV 压力超负荷动物模型的影响。此外，我们还研究了 miR-146a 在人肺动脉平滑肌细胞（hPASMCs）中的过表达。在此，我们发现 miR-146a 的基因表达在 PAH 患者的肺部和单克隆抗体 5415/缺氧（SuHx）和肺动脉结扎（PAB）大鼠的血浆中增加。有趣的是，miR-146a 的基因缺失改善了 SuHx 和 PAB 小鼠的 RV 肥大和收缩压。药理学抑制 miR-146a 改善了 PAB-野生型小鼠和 MCT 大鼠的 RV 重塑，并增强了 MCT 大鼠的运动能力。然而，miR-146a 的过表达并不影响对照-hPASMCs 的增殖、迁移和凋亡。我们的研究结果表明，miR-146a 可能在 RV 功能和重塑中发挥重要作用，是 RV 肥大以及 PAH 的一个有前途的治疗靶点。
