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

ABSTRACT: Background We have reported that cytochrome P450 1B1 ( CYP 1B1), 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 CYP 1B1 to platelet-derived growth factor-BB-induced VSMC migration and proliferation in vitro and to neointimal growth in vivo. Methods and Results VSMC s 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 VSMC s from Cyp1b1 ^-/- mice and in VSMC s 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 CD 68⁺ macrophages and CD 3⁺ 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. Conclusions These data suggest that CYP 1B1-dependent oxidative stress contributes to the neointimal growth caused by wire injury of carotid arteries of male mice.

SUBMITTER: Mukherjee K

PROVIDER: S-EPMC6222936 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Previously, we showed that Cyp1b1 gene disruption minimizes angiotensin II-induced hypertension and associated pathophysiological changes in male mice. This study was conducted to test the hypothesis that cytochrome P450 1B1-generated metabolites of testosterone, 6β-hydroxytestosterone and 16α-hydroxytestosterone, contribute to angiotensin II-induced hypertension and its pathogenesis. Angiotensin II infusion for 2 weeks increased cardiac cytochrome P450 1B1 activity and plasma levels of 6β-hydroxytestosterone, but not 16α-hydroxytestosterone, in Cyp1b1(+/+) mice without altering Cyp1b1 gene expression; these effects of angiotensin II were not observed in Cyp1b1(-/-) mice. Angiotensin II-induced increase in systolic blood pressure and associated cardiac hypertrophy, and fibrosis, measured by intracardiac accumulation of α-smooth muscle actin, collagen, and transforming growth factor-β, and increased nicotinamide adenine dinucleotide phosphate oxidase activity and production of reactive oxygen species; these changes were minimized in Cyp1b1(-/-) or castrated Cyp1b1(+/+) mice, and restored by treatment with 6β-hydroxytestoterone. In Cyp1b1(+/+) mice, 6β-hydroxytestosterone did not alter the angiotensin II-induced increase in systolic blood pressure; the basal systolic blood pressure was also not affected by this agent in either genotype. Angiotensin II or castration did not alter cardiac, angiotensin II type 1 receptor, angiotensin-converting enzyme, Mas receptor, or androgen receptor mRNA levels in Cyp1b1(+/+) or in Cyp1b1(-/-) mice. These data suggest that the testosterone metabolite, 6β-hydroxytestosterone, contributes to angiotensin II-induced hypertension and associated cardiac pathogenesis in male mice, most probably by acting as a permissive factor. Moreover, cytochrome P450 1B1 could serve as a novel target for developing agents for treating renin-angiotensin and testosterone-dependent hypertension and associated pathogenesis in males.

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

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