Elevated microRNA-135a is associated with pulmonary arterial hypertension in experimental mouse model

Abstract

Multiple causes are associated with the complex mechanism of pathogenesis of pulmonary arterial hypertension (PAH), but the molecular pathway in the pathogenesis of PAH is still insufficiently understood. In this study, we investigated epigenetic changes that cause PAH induced by exposure to combined Th2 antigen (Ovalbumin, OVA) and urban particulate matter (PM) in mice. To address that, we focused on the epigenetic mechanism, linked to microRNA (miR)-135a. We found that miR-135a levels were significantly increased, and levels of bone morphogenetic protein receptor type II (BMPR2) which is the target of miR-135a, were significantly decreased in this experimental PAH mouse model. Therefore to evaluate the role of miR-135a, we injected AntagomiR-135a into this mouse model. AntagomiR-135a injected mice showed decreased right ventricular systolic pressures (RVSPs), right ventricular hypertrophy (RVH), and the percentage of severely thickened pulmonary arteries compared to control scrambled miRNA injected mice. Both mRNA and protein expression of BMPR2 were recovered in the AntagomiR-135a injected mice compared to control mice. Our study understands if miR-135a could serve as a biomarker helping to manage PAH. The blocking of miR-135a could lead to new therapeutic modalities to alleviate exacerbation of PAH caused by exposure to Th2 antigen and urban air pollution.

The regulatory role of microRNAs in angiogenesis‐related diseases

“…Functionally, elevated miR‐19a can inhibit arteriogenesis by inhibiting Wnt signalling in vitro and in vivo via directly targeting FZD4 and LRP6,81 and miR‐124 play a major role in glycolysis and hyperproliferation of ECs in PAH by regulating PTBP1 and PKM2 36. In recent studies, miR‐135a levels are up‐regulated in PAH mice models, and miR‐204 and miR‐140‐5p levels are down‐regulated in both PAH patient and PAH model 185, 186. Mechanically, miR‐135a inhibitor can lead to cell death and reduced miR‐140‐5p level can enhance proliferation and migration of PASMCs by increasing SMURF1.…”

“…Mechanically, miR‐135a inhibitor can lead to cell death and reduced miR‐140‐5p level can enhance proliferation and migration of PASMCs by increasing SMURF1. Interestingly, miR‐135a inhibitor, miR‐204 mimics or miR‐140‐5p mimics can significantly prevent the development of PAH, respectively 185, 186. Overall, miRNAs play an important role in the development of PAH and in diagnosis and treatment for PAH.…”

“…Interestingly, miR-135a inhibitor, miR-204 mimics or miR-140-5p mimics can significantly prevent the development of PAH, respectively. 185,186 Overall, miRNAs play an important role in the development of PAH and in diagnosis and treatment for PAH.…”

Insights on the epigenetic mechanisms underlying pulmonary arterial hypertension

“… Experimental mouse model. Lee and Park, 2017 75 miR-140 up-regulated Linked to reduced MFN1 expression in hypertrophic right ventricles from PAH rats. Sugen-5416 injection plus hypoxia exposure-induced PAH rats.…”

Targeting epigenetic mechanisms as an emerging therapeutic strategy in pulmonary hypertension disease

“…One of the proteins, whose expression is tightly regulated by miRNAs, is BMPR2. Indeed, miR-17/29; -21; -20a; -135a; -23a targets BMPR2 and regulates proliferation and differentiation of PASMC and PAECs (122,123,132,145,146). Additionally, miR-322 targets other members of the cascade, namely BMPR1 and Smad5, thus stimulating the proliferation of PASMCs (130).…”