Inhibition of mitogen-mediated proliferation of rat vascular smooth muscle cells by labedipinedilol-A through PKC and ERK 1/2 pathway.

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.

• Authors: Shu-Fen Liou, Jwu-Lai Yeh, Jyh-Chong Liang, Chaw-Chi Chiu, Young-Tso Lin, Ing-Jun Chen
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 44 Issue 5 Pg. 539-51 (Nov 2004) ISSN: 0160-2446 [Print] United States
• PMID: 15505490 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anisoles
• Dihydropyridines
• Isoenzymes
• Platelet-Derived Growth Factor
• Proliferating Cell Nuclear Antigen
• labedipinedilol A
• DNA
• Proline
• Protein-Tyrosine Kinases
• Focal Adhesion Kinase 2
• Ptk2b protein, rat
• Protein Kinase C
• Mitogen-Activated Protein Kinase 1
• MAP Kinase Kinase 2
• Bromodeoxyuridine
• Calcium

Topics

• Animals
• Anisoles (metabolism, pharmacology)
• Aorta, Thoracic (pathology)
• Bromodeoxyuridine (pharmacology)
• Calcium (metabolism)
• Cell Culture Techniques
• Cell Movement (drug effects, genetics)
• Cell Proliferation (drug effects)
• China
• DNA (antagonists & inhibitors, metabolism)
• Dihydropyridines (chemistry, metabolism, pharmacology)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical (methods)
• Focal Adhesion Kinase 2
• Humans
• Interphase (drug effects)
• Isoenzymes (chemistry, metabolism)
• MAP Kinase Kinase 2
• Male
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, drug effects, metabolism)
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Phosphorylation (drug effects)
• Platelet-Derived Growth Factor (metabolism, pharmacology)
• Proliferating Cell Nuclear Antigen (drug effects, genetics, metabolism)
• Proline (chemistry)
• Protein Kinase C (chemistry, metabolism)
• Protein-Tyrosine Kinases (chemistry, metabolism)
• Rats
• Rats, Wistar
• Umbilical Veins (drug effects, metabolism, pathology)