Nrf3-Pla2g7 Interaction Plays an Essential Role in Smooth Muscle Differentiation From Stem Cells

作者：Qingzhong Xiao, Anna Pepe, Gang Wang, Zhenling Luo, Li Zhang, Lingfang Zeng, Zhongyi Zhang, Yanhua Hu, Shu Ye, Qingbo Xu · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2012 · DOI：10.1161/atvbaha.111.243188 · 被引用次数：56 · 研究领域：Pluripotent Stem Cells Research、Protein Kinase Regulation and GTPase Signaling、Genomics, phytochemicals, and oxidative stress

OBJECTIVE: Phospholipase A2, group 7 (Pla2g7) is an important mediator in cardiovascular development and diseases because of its divergent physiological and pathological functions in inflammation and oxidative stress. However, little is known about the functional role of Pla2g7 in smooth muscle cell (SMC) differentiation from stem cells. METHODS AND RESULTS: In the present study, embryonic stem cells were cultivated on collagen IV-coated plates to allow SMC differentiation. Pla2g7 gene expression and activity were upregulated significantly following 4 to 14 days of cell differentiation and colocalized with SMC differentiation markers in the differentiated SMCs. Knockdown of Pla2g7 resulted in downregulation of smooth muscle-specific markers in vitro and impairment of SMC differentiation in vivo, whereas enforced expression of Pla2g7 enhanced SMC differentiation and increased reactive oxygen species generation. Importantly, enforced expression of Pla2g7 significantly increased the binding of serum response factor to SMC differentiation gene promoters, resulting in SMC differentiation, which was abolished by free radical scavenger and flavoprotein inhibitor of NADPH oxidase but not hydrogen peroxide inhibitor. Moreover, we demonstrated that nuclear factor erythroid 2-related factor 3 (Nrf3) regulates Pla2g7 gene expression through direct binding to the promoter regions of Pla2g7 gene. CONCLUSION: Our findings demonstrated that Pla2g7 plays a crucial physiological role in SMC di...