Short-term exposure to low concentrations of thapsigargin inhibits replication of cultured human vascular smooth muscle cells.
BACKGROUND
Central to the pathophysiology of stenosis following balloon angioplasty and arterial bypass surgery is proliferation of vascular smooth muscle cells (VSMCs). To investigate the role of calcium (Ca2+) in VSMC proliferation, the effect of thapsigargin, Ca2+ ionophore A23187, ionomycin, cyclopiazonic acid and di-tert-butylhydroquinone (all of which raise intracellular Ca2+ levels) on the proliferation of cultured human VSMCs was observed.


METHODS
Cultured VSMCs from human saphenous vein were treated with calcium-modulating drugs and proliferation was assessed by determining [3H]thymidine and 5-bromo-2'-deoxyuridine incorporation and cell number.


RESULTS
Over a 48-h exposure, thapsigargin inhibited VSMC replication (median 50 per cent maximal inhibitory concentration 2 nmol/l) whereas the other drugs were much less effective. Short-term exposure (5, 10, 30 and 60 min) to thapsigargin elicited a significant dose-dependent inhibition of VSMC replication whereas, again, the other drugs were without significant effect.


CONCLUSIONS
Thapsigargin-sensitive intracellular Ca2+ pools play a key role in controlling VSMC proliferation and specialized means of administering thapsigargin may constitute a possible approach to preventing stenosis.
Shukla
N
N
University Department of Surgery, Royal Free Hospital and School of Medicine, London, UK.
Jeremy
J Y
JY
Nicholl
P
P
Krijgsman
B
B
Stansby
G
G
Hamilton
G
G
D000328:Adult; D000368:Aged; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D012501:Saphenous Vein; D019284:Thapsigargin / Q000494:pharmacology*; D014648:Varicose Veins / Q000601:surgery
D004791:Enzyme Inhibitors; D006873:Hydroquinones; D007211:Indoles; C019359:2,5-di-tert-butylhydroquinone; D000001:Calcimycin; D015759:Ionomycin; D019284:Thapsigargin; D002118:Calcium; C000543:cyclopiazonic acid