Inhibition of mitogen-mediated proliferation of rat vascular smooth muscle cells by labedipinedilol-A through PKC and ERK 1/2 pathway.
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.
Liou
Shu-Fen
SF
Department of Pharmacology, Kaohsiung Medical University, Kaohsiung, Taiwan.
Yeh
Jwu-Lai
JL
Liang
Jyh-Chong
JC
Chiu
Chaw-Chi
CC
Lin
Young-Tso
YT
Chen
Ing-Jun
IJ
D000818:Animals; D000840:Anisoles / Q000378:metabolism / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000473:pathology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002681:China; D004247:DNA / Q000037:antagonists & inhibitors / Q000378:metabolism; D004095:Dihydropyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051418:Focal Adhesion Kinase 2; D006801:Humans; D007399:Interphase / Q000187:drug effects; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D048370:MAP Kinase Kinase 2; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000840:Anisoles; D004095:Dihydropyridines; D007527:Isoenzymes; D010982:Platelet-Derived Growth Factor; D018809:Proliferating Cell Nuclear Antigen; C500368:labedipinedilol A; D004247:DNA; D011392:Proline; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496054:Ptk2b protein, rat; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048370:MAP Kinase Kinase 2; D001973:Bromodeoxyuridine; D002118:Calcium