Possible Effects And Related Mechanism Of 14q32 MicroRNA MiR-495 On Experimental Pulmonary Arterial Remodeling And Right Ventricular Hypertrophy

Pulmonary Artery Hypertension(PAH)is one disease of human cardiovascular diseases.It is also a clinical hemodynamic syndrome characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance,which can eventually lead to right heart failure and death.Despite the rapid development of targeted drugs for pulmonary vascular remodeling,this kind of carcinomatous disease still has a high mortality rate and poor prognosis.The current mainstream treatment strategy(PAH-specific)focuses on the vascular remodeling of pulmonary vessels,ignoring the whole characteristics of the disease involving multiple other organs.Based on the consciousness of the integrity of pulmonary hypertension,we focused on the expression of 14q32 microRNA gene cluster in pulmonary hypertension---right heart hypertrophy and explored its therapeutic effects.Firstly,the changes of expression about four typical microRNAs in the 14q32 microRNA gene cluster were detected by real-time quantitative qPCR in the mouse HySu pulmonary hypertension model.The result showed that both microRNA-495 and microRNA-487 b have the same trend of upregulation in skeletal muscles and lungs.On the basis of further literature search and bioinformatics analysis,microRNA-495 was selected as the subject of subsequent in vivo intervention studies.Secondly,we explored the effects on pulmonary vascular remodeling after knockdown of miR-495 gene by adeno-associated virus 9 as a vector.The results showed that the pressure of pulmonary hypertension and pulmonary vascular remodeling were significantly reduced.The mechanism may be possibly explained in this way that the expression of microRNA-495 is downregulated in lung tissue,which increases the expression of pulmonary angiogenesis related genes,such as VEZF1,IGF1 and ANG.In vitro cell experiments also showed that down regulation of microRNA-495 could increase the proliferation and migration ability of pulmonary vascular endothelial cells.At last,in the model of monocrotaline induced pulmonary hypertension,we found that the expression of miR-495 was elevated in the hypertrophic right ventricular myocardium and the expression of PTEN protein was down-regulated.Forty-eight hours intervention of Ang II(5 μM)in cultured right ventricular cardiomyocytes successfully established a cardiomyocyte hypertrophic cell model.The following Cell-based intervention experiments have shown that down-regulation of miR-495 expression can alleviate AngII-induced cardiomyocyte hypertrophy.The luciferase reporter gene technique and Western blot analysis consistently showed that miR-495 may be involved in the regulation of right ventricular cardiomyocyte hypertrophy by downregulating the expression of PTEN protein and mediating PI3K/Akt signaling pathway.