Cytochrome P450 1B1 Is Critical for Neointimal Growth in Wire-Injured Carotid Artery of Male Mice.

Abstract

BackgroundWe have reported that cytochrome P450 1B1 (CYP1B1), expressed in cardiovascular tissues, contributes to angiotensin II–induced vascular smooth muscle cell (VSMC) migration and proliferation and development of hypertension in various experimental animal models via generation of reactive oxygen species. This study was conducted to determine the contribution of CYP1B1 to platelet‐derived growth factor‐BB–induced VSMC migration and proliferation in vitro and to neointimal growth in vivo.Methods and Results VSMCs isolated from aortas of male Cyp1b1 +/+ and Cyp1b1 −/− mice were used for in vitro experiments. Moreover, carotid arteries of Cyp1b1 +/+ and Cyp1b1 −/− mice were injured with a metal wire to assess neointimal growth after 14 days. Platelet‐derived growth factor‐BB–induced migration and proliferation and H2O2 production were found to be attenuated in VSMCs from Cyp1b1 −/− mice and in VSMCs of Cyp1b1 +/+ mice treated with 4‐hydroxy‐2,2,6,6‐tetramethylpiperidin‐1‐oxyl, a superoxide dismutase and catalase mimetic. In addition, wire injury resulted in neointimal growth, as indicated by increased intimal area, intima/media ratio, and percentage area of restenosis, as well as elastin disorganization and adventitial collagen deposition in carotid arteries of Cyp1b1 +/+ mice, which were minimized in Cyp1b1 −/− mice. Wire injury also increased infiltration of inflammatory and immune cells, as indicated by expression of CD68+ macrophages and CD3+ T cells, respectively, in the injured arteries of Cyp1b1 +/+ mice, but not Cyp1b1 −/− mice. Administration of 4‐hydroxy‐2,2,6,6‐tetramethylpiperidin‐1‐oxyl attenuated neointimal growth in wire‐injured carotid arteries of Cyp1b1 +/+ mice.ConclusionsThese data suggest that CYP1B1‐dependent oxidative stress contributes to the neointimal growth caused by wire injury of carotid arteries of male mice.