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

Abstract

BackgroundTransplant arteriosclerosis (TA) remains the major cause of chronic graft failure in solid organ transplantation. The phenotypic modulation of vascular smooth muscle 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 γ (PI3Kγ) in VSMC phenotypic modulation and TA.MethodsThe rat model of aortic transplantation was established to detect PI3Kγ expression and its role in neointimal formation and vascular remodeling in vivo. PI3Kγ shRNA transfection was employed to knockdown PI3Kγ gene. Aortic VSMCs was cultured and treated with TNF-α to explore the role and molecular mechanism of PI3Kγ in VSMC phenotypic modulation.FindingsActivated PI3Kγ/p-Akt signaling was observed in aortic allografts and in TNF-α-treated VSMCs. Lentivirus-mediated shRNA transfection effectively inhibited PI3Kγ expression in medial VSMCs while restoring the expression of VSMC contractile genes, associated with impaired neointimal formation in aortic allografts. In cultured VSMCs, PI3Kγ blockade with pharmacological inhibitor or genetic knockdown markedly abrogated TNF-α-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 PI3Kγ inhibition robustly reduced SOX9 expression and its nuclear translocation and repaired the Myocardin/SRF association.InterpretationThese results suggest that PI3Kγ plays a critical role in VSMC phenotypic modulation via a SOX9-dependent mechanism. Therefore, PI3Kγ in VSMCs may represent a promising therapeutic target for the treatment of TA.FundNational Natural Science Foundation of China.

TAK1 accelerates transplant arteriosclerosis in rat aortic allografts by inducing autophagy in vascular smooth muscle cells

“…Moreover, the introduction of smooth muscle-specific conditional deletion by the Cre/lox system suggested a new era in SMC studies [29]. In this study, infection with lentiviruses carrying the Sm22α promoter, as previously described [30], expanded our knowledge on the roles of TAK1 in VSMCs after abdominal aortic transplantation, demonstrating that VSMC-specific deletion of TAK1 attenuated neointima formation after transplantation.…”

“…Conventionally regarded as a regulator of inflammation, TAK1 has also been linked to noninflammatory cell processes in VSMCs, including L-type calcium channel currents [38] and actin polymerization [39], as well as cell proliferation, migration, and autophagic activation, as proven by our results. The contribution of VSMC proliferation and migration to the development of transplant arteriosclerosis has been established [30]. Additionally, the evidence suggests that inflammation and actin polymerization of medial VSMCs contribute to neointima formation [23,40], suggesting that TAK1 may participate in neointima formation by regulating several different cellular processes.…”

CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma

“…2a, b). Interestingly, SOX9 was reported to be regulated by the AKT signaling pathway [35], which is activated by CD73 according to our previous study [23]. Therefore, we speculated that SOX9 could be a key downstream regulator of CD73.…”

CCAAT/Enhancer-Binding Protein Alpha Is a Novel Regulator of Vascular Smooth Muscle Cell Osteochondrogenic Transition and Vascular Calcification

“…Different from the mechanism in endochondral ossification, SOX9 is considered as a key regulator for smooth muscle differentiation. The SOX9-dependent pathway was confirmed to be essential in the TNF-α-induced downregulation of VSMCs contractile genes and the increases in cell proliferation and migration ( Yu et al, 2018 ). Upregulation of SOX9 expression plays a key role in the VSMCs phenotype transdifferentiation and calcification deposition during plaque development ( Augstein et al, 2018 ).…”