51 PLA2g7 mediates smooth muscle cell differentiation from stem cells.
Rationale Phospholipase A2, group 7 (PLA2g7), the plasma isoform of a platelet-activating factor acetylhydrolases, also known as lipoprotein associated phospholipase A2, is a circulating enzyme that catalyse hydrolysis of the sn-2 ester bond of PAF and related pro-inflammatory phospholipids and thus attenuate their bioactivity. However, its involvement in stem cell differentiation has not been studied. Methodology and Results In the present study, we investigated PLA2g7 expression and smooth muscle cells (SMC) differentiation from embryonic stem (ES) cells. PLA2g7 was upregulated significantly in parallel with SMC differentiation genes following 4-14 days of cell differentiation, and colocalisation with SMC differentiation markers in the differentiated ES cells. Knockdown of PLA2g7 resulted in downregulation of smooth muscle specific markers including smooth muscle actin (SMA), SM22, calponin and smooth muscle myosin heavy chain (SMMHC), while enforced expression of PLA2g7 enhanced SMC differentiation and increased ROS generation in a dose-dependent manner. Interestingly, free radical scavenger-N-(2-mercapto-propionyl)-glycine (NMPG) and flavoprotein inhibitor of NADPH oxidase-diphenylene iodonium (DPI), but not hydrogen peroxide inhibitor-catalase, retard PLA2g7-induced SMC differentiation gene expression. Importantly, enforced expression of PLA2g7 significantly increased the binding of SRF to SMC differentiation gene promoters resulting in SMC differentiation. Furthermore, overexpression of Nrf3 resulted in increase of PLA2g7 production, while knockdown Nrf3 ablated the PLA2g7 gene expression and protein activity. Finally, we demonstrated that Nrf3 regulates PLA2g7 gene expression through direct binding to the promoter regions of PLA2g7 gene. Conclusions Our findings demonstrated for the first time that PLA2g7 has a crucial physiological role in SMC differentiation from stem cells, and the fine interactions between Nrf3 and PLA2g7 is essential for ROS balance and SMC differentiation from stem cells. Our data also provide the important insights into the molecular mechanisms of SMC differentiation and cardiovascular development.
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