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PI3K? promotes vascular smooth muscle cell phenotypic modulation and transplant arteriosclerosis via a SOX9-dependent mechanism.

ABSTRACT: BACKGROUND:Transplant 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 ? (PI3K?) in VSMC phenotypic modulation and TA. METHODS:The rat model of aortic transplantation was established to detect PI3K? expression and its role in neointimal formation and vascular remodeling in vivo. PI3K? shRNA transfection was employed to knockdown PI3K? gene. Aortic VSMCs was cultured and treated with TNF-? to explore the role and molecular mechanism of PI3K? in VSMC phenotypic modulation. FINDINGS:Activated PI3K?/p-Akt signaling was observed in aortic allografts and in TNF-?-treated VSMCs. Lentivirus-mediated shRNA transfection effectively inhibited PI3K? expression in medial VSMCs while restoring the expression of VSMC contractile genes, associated with impaired neointimal formation in aortic allografts. In cultured VSMCs, PI3K? blockade with pharmacological inhibitor or genetic knockdown markedly abrogated TNF-?-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? inhibition robustly reduced SOX9 expression and its nuclear translocation and repaired the Myocardin/SRF association. INTERPRETATION:These results suggest that PI3K? plays a critical role in VSMC phenotypic modulation via a SOX9-dependent mechanism. Therefore, PI3K? in VSMCs may represent a promising therapeutic target for the treatment of TA. FUND: National Natural Science Foundation of China.

SUBMITTER: Yu Q

PROVIDER: S-EPMC6197754 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Yu Qihong Q Li Wei W Xie Dawei D Zheng Xichuan X Huang Tong T Xue Ping P Guo Bing B Gao Yang Y Zhang Chen C Sun Ping P Li Min M Wang Guoliang G Cheng Xiang X Zheng Qichang Q Song Zifang Z

EBioMedicine 20180918

<h4>Background</h4>Transplant 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.<h4>Methods</h4>The rat model of aortic transplantation was established to detect ...[more]

PMID: 30241919

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Project description:Background3,3'Diindolylmethane (DIM), a natural phytochemical, has shown inhibitory effects on the growth and migration of a variety of cancer cells; however, whether DIM has similar effects on vascular smooth muscle cells (VSMCs) remains unknown. The purpose of this study was to assess the effects of DIM on the proliferation and migration of cultured VSMCs and neointima formation in a carotid injury model, as well as the related cell signaling mechanisms.Methodology/principal findingsDIM dose-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of VSMCs without cell cytotoxicity. This inhibition was caused by a G0/G1 phase cell cycle arrest demonstrated by fluorescence-activated cell-sorting analysis. We also showed that DIM-induced growth inhibition was associated with the inhibition of the expression of cyclin D1 and cyclin-dependent kinase (CDK) 4/6 as well as an increase in p27(Kip1) levels in PDGF-stimulated VSMCs. Moreover, DIM was also found to modulate migration of VSMCs and smooth muscle-specific contractile marker expression. Mechanistically, DIM negatively modulated PDGF-BB-induced phosphorylation of PDGF-recptor? (PDGF-R?) and the activities of downstream signaling molecules including Akt/glycogen synthase kinase(GSK)3?, extracellular signal-regulated kinase1/2 (ERK1/2), and signal transducers and activators of transcription 3 (STAT3). Our in vivo studies using a mouse carotid arterial injury model revealed that treatment with 150 mg/kg DIM resulted in significant reduction of the neointima/media ratio and proliferating cell nuclear antigen (PCNA)-positive cells, without affecting apoptosis of vascular cells and reendothelialization. Infiltration of inflammatory cells was also inhibited by DIM administration.ConclusionThese results demonstrate that DIM can suppress the phenotypic modulation of VSMCs and neointima hyperplasia after vascular injury. These beneficial effects on VSMCs were at least partly mediated by the inhibition of PDGF-R? and the activities of downstream signaling pathways. The results suggest that DIM has the potential to be a candidate for the prevention of restenosis.

Dataset Information

PI3K? promotes vascular smooth muscle cell phenotypic modulation and transplant arteriosclerosis via a SOX9-dependent mechanism.

Publications

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

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