IL-6 regulates GATA6 gene promoter methylation by activating the JAK2/STAT3 signaling pathway to promote PASMCs proliferation

<bold>Purpose:</bold> The defining feature of pulmonary arterial hypertension (PAH) is pulmonary vascular remodeling caused by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Studies have shown a high expression of IL-6 and a low expression of GATA6 in PAH patients, which play an essential role in the proliferation of PASMCs. The underlying mechanism is still unclear. The purpose of this study is to investigate the relationship between IL-6 and GATA6 in abnormally proliferated PASMCs and their mechanism. <bold>Methods:</bold> The proliferation of PASMCs was induced by PDGF-BB, and the expression of IL-6 and GATA6 were detected. AG490 and 5-Aza were used to intervene in the proliferation of PASMCs induced by PDGF-BB. IL-6-mediated JAK2/STAT3 signal pathway and the level of methylation of GATA6 were analyzed. Finally, IL-6 overexpression/siRNA interference effects on PDGF-BB-induced PASMCs proliferation and the IL-6/JAK2/STAT3 signal pathway together with methylation level of GATA6 gene promoter were detected. <bold>Results:</bold> Abnormally proliferating PASMCs was induced by PDGF-BB. The expression of IL-6 was significantly increased and negatively correlated with the GATA6 mRNA. JAK2/STAT3 inhibition reduced IL-6 expression and methylation of the GATA6 gene. In IL-6-overexpressed PASMCs, the JAK/STAT3 signaling pathway was activated, and the level of GATA6 promoter methylation was increased. After IL-6 siRNA, JAK2/STAT3 signaling pathway and GATA6 methylation were inhibited, and the proliferation of PASMCs was reduced. <bold>Conclusion:</bold> IL-6 regulates GATA6 gene promoter methylation by activating the JAK2/STAT3 signaling pathway to promote PASMCs proliferation.