PI3Kγ promotes vascular smooth muscle cell phenotypic modulation and transplant arteriosclerosis via a SOX9-dependent mechanism

Background: Transplant arteriosderosis (TA) remains the major cause of chronic graft failure in solid organ transplantation. The phenotypic modulation of vascular smooth musde cells (VSMCs) is a key event for the initiation and progression of neointimal formation and TA. This study aims to explore the role and underlying mechanism of phosphoinositide 3-kinases gamma (PI3K gamma) in VSMC phenotypic modulation and TA. Methods: The rat model of aortic transplantation was established to detect PI3K gamma expression and its role in neointimal formation and vascular remodeling in vivo. PI3K gamma shRNA transfection was employed to knockdown PI3K gamma gene. Aortic VSMCs was cultured and treated with TNF-alpha to explore the role and molecular mechanism of PI3K gamma in VSMC phenotypic modulation. Findings: Activated PI3K gamma/p-Akt signaling was observed in aortic allografts and in TNF-alpha-treated VSMCs. Lentivirus-mediated shRNA transfection effectively inhibited PI3K gamma expression in medial VSMCs while restoring the expression of VSMC contractile genes, associated with impaired neointimal formation in aortic allografts. In cultured VSMCs, PI3K gamma blockade with pharmacological inhibitor or genetic knockdown markedly abrogated TNF-alpha-induced downregulation of VSMC contractile genes and increase in cellular proliferation and migration. Moreover. SOX9 located in nucleus competitively inhibited the interaction of Myocardin and SRF, while PI3K gamma inhibition robustly reduced SOX9 expression and its nuclear translocation and repaired the Myocardin/SRF association. Interpretation: These results suggest that PI3K gamma plays a critical role in VSMC phenotypic modulation via a SOX9-dependent mechanism. Therefore, PI3K gamma in VSMCs may represent a promising therapeutic target for the treatment of TA. (C) 2018 Published by Elsevier B.V.