Mechanisms of lysophosphatidic acid-induced DNA synthesis in vascular smooth muscle cells.
In order to investigate the signal transduction mechanisms of lysophosphatidic acid (LPA)-induced vascular smooth muscle (VSM) DNA synthesis, rat aortic A10 cells were used as an experimental model and [ H]-thymidine incorporation was used as an index of DNA synthesis. LPA caused dose- and time-dependent increase in DNA synthesis in A10 VSM cells. LPA (10 microM) also stimulated the activity of casein kinase II (CKII) in a time-dependent manner. The inhibitors of CKII, daidzein and 5,6-dichlorobenzimidazole riboside, diminished the LPA-induced increase in CKII activity and DNA synthesis. The LPA-stimulated activities of extracellularly regulated kinases (ERK) and p38 kinases as well as the stimulatory effects of LPA on DNA synthesis were blocked by ERK inhibitor, PD98059, and p38 kinase inhibitor, SB203580. The LPA-induced increase in intracellular free Ca and the LPA-induced DNA synthesis were not affected by Ca channel blockers, verapamil and diltiazem, as well as a Ca -dependent protein phosphatase (calcineurin) inhibitor, cyclosporine A. These data suggest that the LPA-induced DNA synthesis in VSM cells may be mediated by a signal transduction mechanism involving CKII, ERK, and p38 K.
Xu
Yan-Jun
YJ
Institute of Cardiovascular Sciences, St Boniface General Hospital Research Center, Departments of Physiology and Internal Medicine, University of Manitoba, Winnipeg, Canada.
Rathi
Satyajeet S
SS
Chapman
Donald C
DC
Arneja
Amarjit S
AS
Dhalla
Naranjan S
NS
D000818:Animals; D001011:Aorta; D002118:Calcium / Q000378:metabolism; D047390:Casein Kinase II; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats
D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D004247:DNA; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D002118:Calcium