MicroRNA-137 Inhibited Hypoxia-Induced Proliferation of Pulmonary Artery Smooth Muscle Cells by Targeting Calpain-2

Abstract

The proliferation of pulmonary artery smooth muscle cells (PASMCs) is an important cause of pulmonary vascular remodeling in pulmonary hypertension (PH). It has been reported that miR-137 inhibits the proliferation of tumor cells. However, whether miR-137 is involved in PH remains unclear. In this study, male Sprague-Dawley rats were subjected to 10% O2 for 3 weeks to establish PH, and rat primary PASMCs were treated with hypoxia (3% O2) for 48 h to induce cell proliferation. The effect of miR-137 on PASMC proliferation and calpain-2 expression was assessed by transfecting miR-137 mimic and inhibitor. The effect of calpain-2 on PASMC proliferation was assessed by transfecting calpain-2 siRNA. The present study found for the first time that miR-137 was downregulated in pulmonary arteries of hypoxic PH rats and in hypoxia-treated PASMCs. miR-137 mimic inhibited hypoxia-induced PASMC proliferation and upregulation of calpain-2 expression in PASMCs. Furthermore, miR-137 inhibitor induced the proliferation of PASMCs under normoxia, and knockdown of calpain-2 mRNA by siRNA significantly inhibited hypoxia-induced proliferation of PASMCs. Our study demonstrated that hypoxia-induced downregulation of miR-137 expression promoted the proliferation of PASMCs by targeting calpain-2, thereby potentially resulting in pulmonary vascular remodeling in hypoxic PH.

Crosstalk between ubiquitin ligases and ncRNAs drives cardiovascular disease progression

“…MiR-124-3 reduces cardiomyocyte viability by increasing the expression of the target calpain1, enhancing caspase-3 activity and down-regulating Bcl-2 (137). MiR-137 suppresses the proliferation of hypoxia-induced PASMC and improved PAH by upregulating calpain-2 expression (138). Moreover, Gao, Chen et al (139) found that many miRNAs promote cardiomyocyte autophagy and improve cardiac function by upregulating ATGs (LC3 and beclin-1) and generating autophagosomes.…”

“…MiR-124-3 reduces cardiomyocyte viability by increasing the expression of the target calpain1, enhancing caspase-3 activity and down-regulating Bcl-2 ( 137 ). MiR-137 suppresses the proliferation of hypoxia-induced PASMC and improved PAH by upregulating calpain-2 expression ( 138 ). Moreover, Gao, Chen et al.…”

The Role of Glutamine and Glutaminase in Pulmonary Hypertension

“…Of note, MYC can also influence the activation of mTOR pathway by regulating the metabolic reprogramming of glutamine ( 71 , 72 ). Although the specific contribution of MYC to the metabolic disturbance of PH has not been elucidated, it has been found that MYC activation is related to the proliferation of PAECs and PASMCs ( 5 , 73 ). In addition, recombinant interleukin-6 (IL-6) treatment in rodent models under hypoxia led to pulmonary vascular remodeling, at least in part by MYC activation ( 74 , 75 ).…”