Inhibition of non-Ras protein farnesylation reduces in-stent restenosis.
Ras has a key role in relation to cell proliferation, survival and migration and requires farnesylation for full activity. The effects of a Ras farnesyl transferase inhibitor, FPT III on human atherosclerotic vascular smooth muscle (VSM) cells proliferation and p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) activity was measured. In addition the ability of FPT III to modify the development of neointimal growth was tested in cultured human arteries and in a rabbit model of in-stent restenosis. In human VSM cells FPT III (25 microM) inhibited FCS-stimulated cell proliferation through a ras-dependent mechanism (after 18 h exposure) and also a novel ras-independent mechanism (following 15 min exposure). FPT III incubation (18 h) inhibited platelet-derived growth factor (PDGF)-stimulated p42/p44 MAPK activation and p21 Ras membrane localization, whereas 15 min incubation had no effect on the activation of p42/p44 MAPK in response to PDGF (added at 18 h) or on membrane p21 Ras localization (measured at 18 h). In cultured human atherosclerotic arteries, the presence of 25 microM FPT III significantly reduced neointimal growth. In vivo, 15 min local infusion of 25 microM FPT III significantly reduced in-stent restenosis 28 days later without affecting vascular function in normal rabbit artery. This study demonstrates that brief administration of a farnesyl transferase inhibitor reduced in-stent restenosis in a rabbit model without deleterious effects on vascular function or endothelial regrowth. Acute application of FPT III was found to act through a novel mechanism to inhibit smooth muscle cell proliferation via a non-ras pathway, which may contribute to the prevention of in-stent restenosis.
Division of Physiology and Pharmacology, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, Scotland, UK.
Paul
P
Coats
Simon
S
Kennedy
Susan
S
Pyne
Cherry L
CL
Wainwright
Roger M
RM
Wadsworth
D000368:Aged; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D054855:Drug-Eluting Stents / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032342:Muscle Cells / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology; D063065:Organophosphonates / Q000494:pharmacology*; D010756:Phosphoric Acids / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D011817:Rabbits
C436083:2-(2-oxo-2-((3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy)aminoethyl)phosphonic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester sodium; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D010756:Phosphoric Acids; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D051231:Farnesyltranstransferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3