TSPO ligands prevent the proliferation of vascular smooth muscle cells and attenuate neointima formation through AMPK activation
TSPO ligands prevent the proliferation of vascular smooth muscle cells and attenuate neointima formation through AMPK activation
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TSPO 配体通过 AMPK 激活防止血管平滑肌细胞增殖并减弱新内膜形成
DOI：
10.1038/s41401-019-0293-x
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发表时间：
2019-09
影响因子：
8.2
通讯作者：
Chunyu Zeng
中科院分区：
文献类型：
--
作者：
Lian-pan Wu;Zhengfan Gong;He Wang;Zhou Zhongshu;Ming-ming Zhang;Chao Liu;Hongmei Ren;Jian Yang;Yu Han;Chunyu Zeng
血管内膜层的异常生长（新生内膜形成）有助于动脉粥样硬化和支架内再狭窄的进展。最近的证据表明，18-kDa的转运蛋白（TSPO），线粒体膜蛋白，参与多种心血管疾病。在这项研究中，我们研究了内源性TSPO在体外和体内血管成形术后新生内膜形成中的作用。采用血小板源性生长因子-BB（PDGF-BB）刺激大鼠胸主动脉平滑肌细胞（A10细胞），建立体外血管损伤模型。我们发现用PDGF-BB（1-20 ng/mL）处理以剂量依赖性方式增加A10细胞中的TSPO表达，其在PKC抑制剂或MAPK抑制剂存在下被阻断。过表达TSPO显著促进A10细胞的增殖和迁移，而通过siRNA或用TSPO配体PK 11195或Ro 5 -4864（104 nM）处理下调TSPO表达产生相反的效果。此外，我们发现PK 11195（10-104 nM）剂量依赖性地激活A10细胞中的AMPK。PK 11195诱导的对PDGF-BB处理的A10细胞的增殖和迁移的抑制被化合物C（AMPK特异性抑制剂，103 nM）消除。在球囊损伤颈动脉的大鼠中，TSPO表达在颈动脉中显著上调。从初始球囊损伤开始给予PK 11195（3 mg/kg，每3天一次，ip），持续2周，通过抑制球囊损伤诱导的VSMC表型转换（α-SMA表达增加），极大地减弱了颈动脉新生内膜形成。这些结果表明，TSPO是一种血管损伤反应分子，促进VSMC增殖和迁移，并负责血管损伤后新生内膜的形成，为动脉粥样硬化和再狭窄等多种心血管疾病提供了新的治疗靶点。
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.
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影响因子：
9
作者：
Gatliff J;East DA;Singh A;Alvarez MS;Frison M;Matic I;Ferraina C;Sampson N;Turkheimer F;Campanella M
通讯作者：
Campanella M
影响因子：
39.3
作者：
Gaemperli, Oliver;Shalhoub, Joseph;Camici, Paolo G.
通讯作者：
Camici, Paolo G.
DOI：
10.1007/s00259-008-0919-6
发表时间：
2009-01-01
影响因子：
9.1
作者：
Laitinen, Iina;Marjamaki, Paivi;Knuuti, Juhani
通讯作者：
Knuuti, Juhani
影响因子：
3.6
作者：
Wang, Hui-Jie;Fan, Jinjiang;Papadopoulos, Vassilios
通讯作者：
Papadopoulos, Vassilios
影响因子：
13.5
作者：
Guilarte TR
通讯作者：
Guilarte TR