1. Inhibition of mitogen-mediated proliferation of rat vascular smooth muscle cells by labedipinedilol-A through PKC and ERK 1/2 pathway.
- Author
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Liou SF, Yeh JL, Liang JC, Chiu CC, Lin YT, and Chen IJ
- Subjects
- Animals, Anisoles metabolism, Aorta, Thoracic pathology, Bromodeoxyuridine pharmacology, Calcium metabolism, Cell Culture Techniques, Cell Movement drug effects, Cell Movement genetics, Cell Proliferation drug effects, China, DNA antagonists & inhibitors, DNA metabolism, Dihydropyridines chemistry, Dihydropyridines metabolism, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical methods, Focal Adhesion Kinase 2, Humans, Interphase drug effects, Isoenzymes chemistry, Isoenzymes metabolism, MAP Kinase Kinase 2, Male, Mitogen-Activated Protein Kinase 1 drug effects, Mitogen-Activated Protein Kinase 1 metabolism, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular metabolism, Phosphorylation drug effects, Platelet-Derived Growth Factor metabolism, Platelet-Derived Growth Factor pharmacology, Proliferating Cell Nuclear Antigen drug effects, Proliferating Cell Nuclear Antigen genetics, Proliferating Cell Nuclear Antigen metabolism, Proline chemistry, Protein Kinase C chemistry, Protein-Tyrosine Kinases chemistry, Protein-Tyrosine Kinases metabolism, Rats, Rats, Wistar, Umbilical Veins drug effects, Umbilical Veins metabolism, Umbilical Veins pathology, Anisoles pharmacology, Dihydropyridines pharmacology, Mitogen-Activated Protein Kinase 1 antagonists & inhibitors, Muscle, Smooth, Vascular pathology, Protein Kinase C metabolism
- Abstract
Labedipinedilol-A is a novel 1, 4-dihydropyridine type calcium antagonist with alpha-receptor blocking activity. This study investigates the effects of labedipinedilol-A on mitogen-induced proliferation of rat vascular smooth muscle cells (VSMCs). Labedipinedilol-A's inhibition on cell proliferation was measured by the tetrazolium salt (XTT) test. Labedipinedilol-A dose-dependently inhibited mitogen-induced DNA synthesis, determined by the incorporation of 5-bromo-2'-deoxyuridine (BrdU). Labedipinedilol-A was also found capable of inhibiting the migration of VSMCs induced by PDGF-BB with an IC50 value of 5.6 microM. In accordance with these findings, labedipinedilol-A revealed blocking of the FBS-inducible progression through G0/G1 to S phase of the cell cycle in synchronized cells. Labedipinedilol-A appeared to cause inhibition of mitogens-induced PKC translocation, suggesting the probable involvement of protein kinase C (PKC) in this cellular response. Labedipinedilol-A reduced both intracellular Ca and the phosphorylation of extracellular signal-regulated protein kinase 1/2 in PDGF-BB-stimulated VSMCs. It also suppressed the levels of proliferative cell nuclear antigen (PCNA) in VSMCs both time- and dose-dependently. These results indicate that labedipinedilol-A may inhibit cell proliferation by attenuating activation of the ERK 1/2 pathway, which is regulated by PKC and Ca, suggesting that it may have great potential in the prevention of progressive atherosclerosis.
- Published
- 2004
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