Non-muscle myosin light chain promotes endothelial progenitor cells senescence and dysfunction in pulmonary hypertensive rats through up-regulation of NADPH oxidase

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• 作者：Bin Liu^a ; ^b ; ¹ ; Tao Li^a ; ^c ; ¹ ; Jing-Jie Peng^a ; ^d ; Jie-Jie Zhang^a ; Wei-Qi Liu^e ; Xiu-Ju Luo^d ; Qi-Lin Ma^e ; Zhi-Cheng Gong^b ; Jun Peng^a ; ^c ; ^{Junpeng@csu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Non-muscle myosin regulatory light chain (nmMLC20) ; Endothelial progenitor cell (EPC) ; Senescence ; NAPDH oxidase ; Pulmonary arterial hypertension
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 March 2016
• 年：2016
• 卷：775
• 期：Complete
• 页码：67-77
• 全文大小：4592 K

文摘

Non-muscle myosin regulatory light chain (nmMLC₂₀) is reported to exert transcriptional function in regulation of gene expression, and NADPH oxidase (NOX)-derived reactive oxygen species contribute to vascular remodeling of pulmonary artery hypertension (PAH). This study aims to determine if nmMLC₂₀ can promote endothelial progenitor cells (EPCs) senescence and dysfunction through up-regulation of NOX in PAH rats. The rats were exposed to10% hypoxia for 3 weeks to establish a PAH model, which showed an increase in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, and the accelerated senescence and impaired functions in EPCs, accompanied by an increase in Rho-kinase (ROCK) and NOX activities, p-nmMLC₂₀ level, NOX expression and H₂O₂ content; these phenomena were reversed by fasudil, a selective inhibitor of ROCK. Next, normal EPCs were cultured under hypoxia to induce senescence in vitro. Consistent with the in vivo findings, hypoxia increased the senescence and dysfunction of EPCs concomitant with an increase in ROCK and NOX activities, p-nmMLC₂₀ level, NOX expression and H₂O₂ content; these phenomena were reversed by fasudil. Knockdown of nmMLC₂₀ showed similar results to that of fasudil except no effect on ROCK activity. Based on these observations, we conclude that nmMLC₂₀ could promote the senescence and dysfunctions of EPCs in PAH through up-regulation of NOX in a phosphorylation-dependent manner.