Cilazapril suppresses myointimal proliferation after vascular injury: effects on growth factor induction in vascular smooth muscle cells.
Smooth muscle cell proliferation and formation of extracellular matrix in the intima of muscular arteries after vascular injury can lead to severe intimal hyperplasia and stenosis. Cilazapril reduces intimal hyperplasia induced by balloon catheterization of the rat carotid artery by 80%, and significantly decreases the surface area covered by proliferative lesions. We investigated the effects of angiotensin II (A II) on SMC proliferation in cell culture and A-II induction of selected growth factor or growth-related genes in SMC in culture: PDGF A chain, TGF-beta, thrombospondin, c-myc and c-fos, and compared the influence of cilazapril on these responses to A II. A-II induced SMC proliferation, stimulated mRNAs for c-myc and c-fos after 30 min, and stimulated mRNAs for PDGF A chain, TGF-beta, and thrombospondin somewhat later. The ACE inhibitor did not have detectable independent effects on the A-II induced proliferation or gene expression. Thus, these data support the conclusion that cilazapril suppresses SMC proliferation in vivo through the block of conversion of A I to A II, and that A II has a critical and central role in the control of the proliferative response after balloon catheter-induced vascular injury.
Powell
J S
JS
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Rouge
M
M
Müller
R K
RK
Baumgartner
H R
HR
D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017315:Cilazapril; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011724:Pyridazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats
D000806:Angiotensin-Converting Enzyme Inhibitors; D006133:Growth Substances; D011724:Pyridazines; D012333:RNA, Messenger; D000804:Angiotensin II; D017315:Cilazapril