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

Authors: Lian-pan Wu1,2, Zheng-fan Gong1,2, He Wang1,2, Zhong-shu Zhou1,2, Ming-ming Zhang1,2, Chao Liu1,2, Hong-mei Ren1,2, Jian Yang1,2, Yu Han1,2, Chun-yu Zeng1,2
1 Department of Cardiology, Daping Hospital, The Third Military Medical University, Chongqing 400042, China
2 Chongqing Institute of Cardiology & Chongqing Key Laboratory of Hypertension Research, Chongqing 400042, China
Correspondence to: Yu Han:, Chun-yu Zeng:,
DOI: 10.1038/s41401-019-0293-x
Received: 7 March 2019
Accepted: 17 July 2019
Advance online: 12 September 2019


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.
Keywords: neointima formation; vascular smooth muscle cells; proliferation; TSPO; AMPK; PDGF-BB; PK11195; Ro5-4864; compound C; balloon-injured carotid arteries

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