TSPO ligands prevent the proliferation of vascular smooth muscle cells and attenuate neointima formation through AMPK activation
Open accessAbstract
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 (10 4 nM) produced the opposite effects. Furthermore, we found that PK11195 (10-10 4 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, 10 3 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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Supplementation of PK11195 markedly reduced neointima formation in carotid arteries after balloon injury, through the suppression of the phenotype switching of VSMC.
“Supplementation of PK11195, a ligand of TSPO, markedly reduced neointima formation in carotid arteries after balloon injury, through the suppression of the phenotype switching of VSMC [137].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [137]
TSPO is involved in the aberrant VSMC proliferation after angioplasty.
“The translocator protein (TSPO), an 18 kDa protein located at the outer mitochondrial membrane, is involved in the aberrant VSMC proliferation after angioplasty [137].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [137]
TSPO regulates neointimal formation after vascular injury via stimulating VSMC proliferation and migration, which is likely dependent on AMPK suppression.
“These results indicate that TSPO regulates neointimal formation after vascular injury via stimulating VSMC proliferation and migration, which is likely dependent on AMPK suppression [137].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [137]
AMPK-specific inhibitor compound C abolished PK11195-induced inhibition of the proliferation and migration of platelet-derived growth factor-BB-treated A10 cells.
“An AMPK-specific inhibitor, compound C, abolished PK11195-induced inhibition of the proliferation and migration of platelet-derived growth factor-BB-treated A10 cells [137].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [137]
PK11195 activated AMPK in A10 cells in a dose-dependent manner.
“Furthermore, it was found that PK11195 activated AMPK in A10 cells in a dose-dependent manner.”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [137]
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References 37 · Cited by 12
- Authors
- Wu, L.-P., Gong, Z.-F., Wang, H., Zhou, Z.-S., Zhang, M.-M., Liu, C., Ren, H.-M., Yang, J., Han, Y., & Zeng, C.-Y.
- Affiliations
- Army Medical University (CN)
- Corresponding author
- Han, Yu
- Venue
- Acta Pharmacologica Sinica
- Published
- 2019-09-12
- Volume
- 41
- Issue
- 1
- Pages
- 34-46
- ISSN
- 0253-9756 (ISSN-L)
- 1671-4083
- 1745-7254
- PMC
- PMC7471478
- OpenAlex
- W2972629906
- Cited by
- 12
- References
- 37
- Citations by year
- 2024: 5 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 2
- FWCI
- 0.50
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-12-09)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Acta Pharmacologica Sinica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81770425, IRT1216, 2018YFC1312700, 31730043, 81721001)
- Program for Changjiang Scholars and Innovative Research Team in University (IRT1216)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Surgery › Coronary Interventions and Diagnostics
- Keywords
- translocator protein (TSPO), neointima formation, vascular smooth muscle cell proliferation, cell migration, AMPK activation, PK11195, Ro5-4864, PDGF-BB, vascular injury, balloon injury, atherosclerosis, in-stent restenosis, alpha-smooth muscle actin, protein kinase C, mitogen-activated protein kinase, carotid artery
- MeSH terms
- Becaplermin, Animals, Benzodiazepinones, Cell Movement, Cells, Cultured, Enzyme Activation, Humans, Isoquinolines, Ligands, Male, Muscle, Smooth, Vascular, Rats, Sprague-Dawley, Receptors, GABA, Cell Proliferation, Rats, AMP-Activated Protein Kinases, Neointima
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