Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Abstract

Cytochrome P450 (CYP) 1B1 is implicated in vascular smooth muscle cell migration, proliferation, and hypertension. We assessed the contribution of CYP1B1 to angiotensin (Ang) IIeinduced abdominal aortic aneurysm (AAA). Male Apoe À/À /Cyp1b1 þ/þ and Apoe À/À /Cyp1b1 À/À mice were infused with Ang II or its vehicle for 4 weeks; another group of Apoe À/À /Cyp1b1 þ/þ mice was coadministered the CYP1B1 inhibitor 2,3 0 ,4,5 0 -tetramethoxystilbene (TMS) every third day for 4 weeks. On day 28 of Ang II infusion, AAAs were analyzed by ultrasound and ex vivo by Vernier calipers, mice were euthanized, and tissues were harvested. Ang II produced AAAs in Apoe À/À /Cyp1b1 þ/þ mice; mice treated with TMS or Apoe À/À /Cyp1b1 À/À mice had reduced AAAs. Ang II enhanced infiltration of macrophages, T cells, and platelets and increased plateletderived growth factor D, Pdgfrb, Itga2, and matrix metalloproteinases 2 and 9 expression in aortic lesions; these changes were inhibited in mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice. Oxidative stress resulted in cyclooxygenase-2 expression in aortic lesions. These effects were minimized in Apoe À/À / Cyp1b1 þ/þ mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice and by concurrent treatment with the superoxide scavenger 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl. CYP1B1 contributed to the development of Ang IIeinduced AAA and associated pathogenic events in mice, likely by enhancing oxidative stress and associated signaling events. Thus, CYP1B1 may serve as a target for therapeutic agents for AAA in males. (Am J Pathol 2016 http://dx

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

“…Strikingly, the most prominent difference in elastin remodeling between Cyp1b1 +/+ and Cyp1b1 −/− mice was observed in grades 3 and 4 of the elastin degradation index, implying that a breakage of elastin fibers in Cyp1b1 +/+ mice might have permitted medial SMCs to breach the ECM and migrate to form neointima. These results, coupled with our in vitro findings of attenuated migration of VSMCs by Cyp1b1 gene disruption, along with our previous work in mouse models of atherosclerosis and abdominal aortic aneurysms,28, 29 indicate that CYP1B1 plays an important role in elastin metabolism/degradation . …”

“…Our finding that the CYP1B1 inhibitor 2,3′,4,5′‐tetramethoxystilbene minimizes hypertension, atherosclerosis, and abdominal aneurysms,5, 28, 29 while also attenuating neointimal growth in wire‐injured carotid artery of Cyp1b1 +/+ male mice, further supports our hypothesis that CYP1B1 is required for neointimal growth and suggests an important translational implication of this work. Thus, CYP1B1 could serve as a potential target for the development of novel agents for the treatment of restenosis after balloon angioplasty, or to coat drug‐eluting stents as antiproliferative agents in male mice.…”

“…We have previously reported that ROS generated via CYP1B1 contribute to the development of hypertension in different animal models, atherosclerosis, and abdominal aortic aneurysms 5, 28, 29. In the current study, wire injury of the carotid arteries increased superoxide production, as detected by 2‐hydroxyethidium fluorescence in Cyp1b1 +/+ mice, which was reduced in Cyp1b1 −/− mice.…”

“…The neoadventitia formation is one of the earliest events after vascular injury34 and hence can be used as an alternative predictor of carotid artery disease 35. We have reported that CYP1B1 plays a critical role in collagen deposition and fibrosis in several tissues in hypertension, and in atherosclerosis and abdominal aortic aneurysms 28, 29, 36. Adventitial fibrosis associated with vascular injury also requires CYP1B1, and Cyp1b1 gene disruption decreased adventitial collagen deposition in injured mouse carotid arteries.…”

CYP1B1 as a therapeutic target in cardio-oncology

“…On the other hand, the protective effects of CYP1B1 in female rodents have been attributed to CYP1B1-mediated metabolism of estrogen to 2-methoxyestradiol [ 96 , 97 ]. Furthermore, CYP1B1 has been shown to contribute to the development of atherosclerosis, hypertension, and angiotensin II-induced aortic aneurysm in male apolipoprotein E-deficient mice [ 98 , 99 ]. In vitro studies have suggested the contribution of CYP1B1-mediated formation of genotoxic metabolites and DNA adducts in the development of atherosclerosis by polyaromatic hydrocarbons [ 100 , 101 ].…”