Mutated p21/WAF/CIP transgene overexpression reduces smooth muscle cell proliferation, macrophage deposition, oxidation-sensitive mechanisms, and restenosis in hypercholesterolemic apolipoprotein E knockout mice

We have investigated whether by introducing a mutated p21 cyclin-dependent kinase inhibitor through a standard type 5 adenovirus (Ad), it would be pos sible to interfere with restenosis in hypercholesterolemic apolipoprotein E knockout mice. Restenosis is a clinically relevant, undesired effect of pe rcutaneous transluminal coronary angioplasty (PTCA). A critical event under lying restenosis is smooth muscle cell (SMC) proliferation leading to neoin timal formation and vessel reocclusion. Recent data demonstrated that it is possible to reduce restenosis by introducing various genes blocking the ce ll cycle through Ad vectors. Nonetheless, most experiments were conducted i n the healthy carotid artery of rat, which is far from the condition of hum an disease. Therefore, we investigated whether antiproliferative or proapop totic genes affect restenosis in a model of atherosclerosis closer to clini cal settings. Ad-mutated(m)-p21WAF/CIP1 transgene overexpression induces a significant reduction of restenosis in hypercholesterolemic apolipoprotein E knockout mice subjected to injury of common carotid artery. This was asso ciated with reduced SMC density and proliferation, macrophage deposition, a nd oxidation-sensitive mechanisms. Treatment with p21/WAF also enhanced TUN EL positivity of arterial cells. We show that in an experimental model of a therosclerosis, braking the cell proliferation through increased vascular a poptosis and reduced oxidation-sensitive signal transduction and macrophage accumulation can significantly ameliorate the deleterious effects of vascu lar injuries similar to those that occur during PTCA and related procedures .