MiR‐17~92 promotes hypoxia‐induced pulmonary hypertension by regulating proliferation and contraction of pulmonary arterial smooth muscle cells (LB779)

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Introduction: Recent studies suggest that microRNAs (miRNAs) play important roles in development and pathogenesis of human diseases. We sought to identify novel miRNAs that may be involved in the pathogenesis of pulmonary arterial hypertension (PAH) and to investigate underlying mechanisms.Methods and Results: We performed miRNA qPCR array using pulmonary arterial smooth muscle cells (PASMC) isolated from lungs of normal donor and PAH patients. We found that all of the six members of the miR‐17~92 cluster were down‐regulated in PAH PASMCs. In hypoxia‐induced PAH mouse model and cultured human PASMCs, we found that short term hypoxia induced miR‐17~92 whereas prolonged hypoxia suppressed miR‐17~92. We generated a strain of SMC‐specific miR‐17~92 knockout (sm‐17~92‐/‐) mouse by crossbreeding miR‐17~92 fl/fl mice with sm22α‐Cre mice and subsequent backcrossing. We exposed 8‐10 week old sm‐17~92‐/‐ mice along with their wild type littermates to hypoxia (10% O2) or normoxia for five weeks. We showed that knockout of miR‐17~92 in SMC attenuated hypoxia‐induced increase in measured their right ventricular systolic pressure (RVSP), RV hypertrophy (RV/(LV+S) ratio), and pulmonary arterial wall thickness, suggesting that SMC‐specific miR‐17~92 is essential for the development of PAH. To investigate the underlying mechanism, we over‐expressed the miR‐17~92 cluster in human PASMC by a lenti‐virus encoding this miRNA cluster. Overexpression of mi‐17~92 induced expression levels of SMA, SM22α, Calponin, and PCNA and BrdU incorporation. Human PASMC from idiopathic PAH (IPAH) patients expressed decreased levels of SMA, SM22α, and Calponin, whereas over‐expression of miR‐17~92 restored the expression of SMA, SM22α, and Calponin in PASMCs from IPAH patient.Summary: We provide evidence that miR‐17~92 is dysregulated in hypertensive PASMC and suppression miR‐17~92 in SMC is sufficient to inhibit hypoxia‐induced PAH in vivo. We also show that miR‐17~92 induces PASMC proliferation and expression of contractile proteins. These results suggest that miR‐17~92 may promote PAH by regulating vascular remodeling and that miR‐17~92 may represent a novel therapeutic target for the treatment of PAH. Support: NIH HL110829 and Gilead Sciences Research Scholars Program.Grant Funding Source: Support by NIH HL110829 and Gilead Sciences Research Scholars Program.