Inhibition of microRNA-30a alleviates vascular remodeling in pulmonary arterial hypertension

Abstract

The excessive and ectopic pulmonary artery smooth muscle cells (PASMCs) are crucial to the pathogenesis of pulmonary arteriole (PA) remodeling in pulmonary arterial hypertension (PAH). We previously found that microRNA (miR)-30a was significantly increased in acute myocardial infarction (AMI) patients and animals, as well as in cultured cardiomyocytes after hypoxia, suggesting that it might be strongly associated with hypoxia-related diseases. Here, we investigated the role of miR-30a in the PASMC remodeling of PAH. The expression of miR-30a was higher in the serum of PAH patients compared with healthy controls. miR-30a was mainly expressed in PAs and was increased in PASMCs after hypoxia, mediating the downregulation of p53 tumor suppressor protein (P53). Genetic knockout of miR-30a effectively decreased right ventricular (RV) systolic pressure (RVSP), PA, and RV remodeling in the Su5416/hypoxia-induced and monocrotaline (MCT)-induced PAH animals. Additionally, pharmacological inhibition of miR-30a via intratracheal liquid instillation (IT-L) delivery strategy showed high efficiency, which downregulated miR-30a to mitigate disease phenotype in the Su5416/hypoxiainduced PAH animals, and these beneficial effects could be partially reduced by simultaneous P53 inhibition. We demonstrate that inhibition of miR-30a could ameliorate experimental PAH through the miR-30a/P53 signaling pathway, and the IT-L delivery strategy shows good therapeutic outcomes, providing a novel and promising approach for the treatment of PAH.

FUT8-Mediated Core Fucosylation Promotes the Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

“…Pulmonary outer membrane fibroblasts, the extracellular matrix, and inflammatory cells are involved in this progress, but the thickening of the middle membrane caused by the excessive proliferation and apoptosis resistance of PASMCs is the most important factor leading to pulmonary vascular remodeling [26][27][28][29][30]. Accordingly, scholars have studied PASMCs by exploring the effect of traditional Chinese medicine [31][32][33][34][35][36], and the roles of molecules related to tumors and other diseases [37][38][39][40], as well as the effect of noncoding RNAs, such as microRNAs and LncRNAs on PASMC phenotypic changes [41][42][43][44][45][46][47][48].…”

Non-coding RNAs function as diagnostic biomarkers and therapeutic targets in pulmonary arterial hypertension

“…In animal models of HySu-induced and MCT-induced PAH, genetic knockout of the miR-30a gene effectively reduces right ventricular systolic blood pressure (RVSP), as well as attenuates remodeling of the pulmonary arteriole and hypertrophy of the right ventricle. Furthermore, pharmacological inhibition of miR-30a through intratracheal fluid perfusion (IT-L) administration strategy demonstrates high efficacy [46].…”

Pulmonary Delivery for miRs: Present and Future Potential

“…The authors intratracheally nebulized miR-204 mimic along with Invivofectamine for administration to rats, and the treatment decreased disease severity in male rats with induced pulmonary arterial hypertension. In a recent study on pulmonary arterial hypertension, Ma et al [177] evaluated the inhibition of miR-30a for treating the disease. The authors used miR-30a inhibitors and mimics to assess the activity of the miR in vitro using lipofectamine 3000, while they used naked miR mimics and inhibitors in PBS for in vivo administration through intratracheal instillation.…”