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TSPO ligands prevent the proliferation of vascular smooth muscle cells and attenuate neointima formation through AMPK activation.

Abstract：

:Abnormal growth of the intimal layer of blood vessels (neointima formation) contributes to the progression of atherosclerosis and in-stent restenosis. Recent evidence shows that the 18-kDa translocator protein (TSPO), a mitochondrial membrane protein, is involved in diverse cardiovascular diseases. In this study we investigated the role of endogenous TSPO in neointima formation after angioplasty in vitro and in vivo. We established a vascular injury model in vitro by using platelet-derived growth factor-BB (PDGF-BB) to stimulate rat thoracic aortic smooth muscle cells (A10 cells). We found that treatment with PDGF-BB (1-20 ng/mL) dose-dependently increased TSPO expression in A10 cells, which was blocked in the presence of PKC inhibitor or MAPK inhibitor. Overexpression of TSPO significantly promoted the proliferation and migration in A10 cells, whereas downregulation of TSPO expression by siRNA or treatment with TSPO ligands PK11195 or Ro5-4864 (104 nM) produced the opposite effects. Furthermore, we found that PK11195 (10-104 nM) dose-dependently activated AMPK in A10 cells. PK11195-induced inhibition on the proliferation and migration of PDGF-BB-treated A10 cells were abolished by compound C (an AMPK-specific inhibitor, 103 nM). In rats with balloon-injured carotid arteries, TSPO expression was markedly upregulated in the carotid arteries. Administration of PK11195 (3 mg/kg every 3 days, ip), starting from the initial balloon injury and lasting for 2 weeks, greatly attenuated carotid neointima formation by suppressing balloon injury-induced phenotype switching of VSMCs (increased α-SMA expression). These results suggest that TSPO is a vascular injury-response molecule that promotes VSMC proliferation and migration and is responsible for the neointima formation after vascular injury, which provides a novel therapeutic target for various cardiovascular diseases including atherosclerosis and restenosis.

journal_name

Acta Pharmacol Sin

journal_title

Acta pharmacologica Sinica

authors

Wu LP,Gong ZF,Wang H,Zhou ZS,Zhang MM,Liu C,Ren HM,Yang J,Han Y,Zeng CY

doi

10.1038/s41401-019-0293-x

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

34-46

issue

eissn

1671-4083

issn

1745-7254

pii

10.1038/s41401-019-0293-x

journal_volume

pub_type

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TSPO ligands prevent the proliferation of vascular smooth muscle cells and attenuate neointima formation through AMPK activation.