ArticleToxicology and applied pharmacology2012
Verapamil stereoisomers induce antiproliferative effects in vascular smooth muscle cells via autophagy.
Article in Toxicology and applied pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
- Calcium and TRPML-Mediated Autophagy: Implications in Cancer, Cardiovascular Diseases, and Cardio-Oncology.Cardiovascular toxicology · 2026Review
- Acousto-optogenetics bandpass stabilizer: A programmable platform for mapping single-cell phenotypic life trajectories.Materials today. Bio · 2025Article
- Coronary and carotid artery dysfunction and KGeroScience · 2024Article
- Mitochondrial Dysfunction in Cardiac Diseases and Therapeutic Strategies.Biomedicines · 2023Review
- Sox9 mediates autophagy-dependent vascular smooth muscle cell phenotypic modulation and transplant arteriosclerosis.iScience · 2022Article
- Caffeine prevents restenosis and inhibits vascular smooth muscle cell proliferation through the induction of autophagy.Autophagy · 2022Article
- Review
- Everolimus Rescues the Phenotype of Elastin Insufficiency in Patient Induced Pluripotent Stem Cell-Derived Vascular Smooth Muscle Cells.Arteriosclerosis, thrombosis, and vascular biology · 2020Article
- Activation of TFEB ameliorates dedifferentiation of arterial smooth muscle cells and neointima formation in mice with high-fat diet.Cell death & disease · 2019Article
- [Regulatory role of autophagy in development of pulmonary artery hypertension].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2018Article
- Myocardial stress and autophagy: mechanisms and potential therapies.Nature reviews. Cardiology · 2017Review
- The Anti-atherosclerotic Effect of Paeonol against Vascular Smooth Muscle Cell Proliferation by Up-regulation of Autophagy via the AMPK/mTOR Signaling Pathway.Frontiers in pharmacology · 2017Article
- Metformin induces degradation of mTOR protein in breast cancer cells.Cancer medicine · 2016Article
- In vitro and in silico analysis of the vascular effects of asymmetrical N,N-bis(alkanol)amine aryl esters, novel multidrug resistance-reverting agents.Naunyn-Schmiedeberg's archives of pharmacology · 2016Article
- Increased MFG-E8 expression and its implications in the vascular pathophysiology of cocaine abuse.Journal of toxicologic pathology · 2016Article
- ORMDL3 contributes to the risk of atherosclerosis in Chinese Han population and mediates oxidized low-density lipoprotein-induced autophagy in endothelial cells.Scientific reports · 2015Article
- Autophagic regulation of smooth muscle cell biology.Redox biology · 2015Review
- The role of oxidative stress and autophagy in atherosclerosis.Oxidative medicine and cellular longevity · 2015Review
- Autophagy in cardiovascular biology.The Journal of clinical investigation · 2015Review
- Implications of autophagy for vascular smooth muscle cell function and plasticity.Free radical biology & medicine · 2013Review
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Calcium channel blockers (CCBs) are important in the management of hypertension and limit restenosis. Although CCB efficacy could derive from decreased blood pressure, other mechanisms independent of CCB activity also can contribute to antiproliferative action. To understand mechanisms of CCB-mediated antiproliferation, we studied two structurally dissimilar CCBs, diltiazem and verapamil, in cultured rat vascular smooth muscle cells (VSMC). To elucidate CCB-independent effects, pure stereoisomers of verapamil (R-verapamil, inactive VR; S-verapamil, active, VS) were used. The effects of CCB exposure on cell viability (MTT reduction), cell proliferation ((3)H-thymidine incorporation), VSMC morphology by light and transmission electron microscopy (TEM) and autophagy (LC3I/II, ATG5) were measured. In general, verapamil, VR or VS treatment alone (80 μM) appreciably enhanced MTT absorbance although higher concentrations (VR or VS) slightly decreased MTT absorbance. Diltiazem (140 μM) markedly decreased MTT absorbance (40%) at 120 h. VR or VS treatment inhibited (3)H-thymidine incorporation (24h) and induced cytological alterations (i.e., karyokinesis, enhanced perinuclear MTT deposition, accumulated perinuclear "vacuoles"). TEM revealed perinuclear "vacuoles" to be aggregates of highly laminated and electron-dense vesicles resembling autophagosomes and lysosomes, respectively. Increased autophagosome activity was confirmed by a concentration-dependent increase in LC3-II formation by Western blotting and by increased perinuclear LC3-GFP(+) puncta in verapamil-treated VSMC. Verapamil stereoisomers appeared to decrease perinuclear mitochondrial density. These observations indicate that antiproliferative effects of verapamil stereoisomers are produced by enhanced mitochondrial damage and upregulated autophagy in VSMC. These effects are independent of CCB activity indicating a distinct mechanism of action that could be targeted for more efficacious anti-atherosclerotic and anti-restenosis therapy.
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