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

Shyamala Thirunavukkarasu, Nayaab S. Khan, Chi Young Song, Hafiz U. Ghafoor, David Brand, Frank J. Gonzalez, Kafait Malik

Research output: Contribution to journalArticle

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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) II–induced abdominal aortic aneurysm (AAA). Male Apoe−/−/Cyp1b1+/+ and Apoe−/−/Cyp1b1−/− mice were infused with Ang II or its vehicle for 4 weeks; another group of Apoe−/−/Cyp1b1+/+ mice was coadministered the CYP1B1 inhibitor 2,3′,4,5′-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−/−/Cyp1b1+/+ mice; mice treated with TMS or Apoe−/−/Cyp1b1−/− mice had reduced AAAs. Ang II enhanced infiltration of macrophages, T cells, and platelets and increased platelet-derived 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−/−/Cyp1b1−/− mice. Oxidative stress resulted in cyclooxygenase-2 expression in aortic lesions. These effects were minimized in Apoe−/−/Cyp1b1+/+ mice treated with TMS and in Apoe−/−/Cyp1b1−/− 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 II–induced 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.

Original languageEnglish (US)
Pages (from-to)2204-2219
Number of pages16
JournalAmerican Journal of Pathology
Volume186
Issue number8
DOIs
StatePublished - Aug 1 2016

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Aortic Aneurysm
Angiotensins
Apolipoproteins E
Cytochrome P-450 Enzyme System
Angiotensin II
Abdominal Aortic Aneurysm
Oxidative Stress
Platelet-Derived Growth Factor
Matrix Metalloproteinase 9
Cyclooxygenase 2
Vascular Smooth Muscle
Superoxides
Hydroxyl Radical
Smooth Muscle Myocytes
Cell Movement
Blood Platelets
Macrophages
Cell Proliferation
Hypertension
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice. / Thirunavukkarasu, Shyamala; Khan, Nayaab S.; Song, Chi Young; Ghafoor, Hafiz U.; Brand, David; Gonzalez, Frank J.; Malik, Kafait.

In: American Journal of Pathology, Vol. 186, No. 8, 01.08.2016, p. 2204-2219.

Research output: Contribution to journalArticle

Thirunavukkarasu, Shyamala ; Khan, Nayaab S. ; Song, Chi Young ; Ghafoor, Hafiz U. ; Brand, David ; Gonzalez, Frank J. ; Malik, Kafait. / Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice. In: American Journal of Pathology. 2016 ; Vol. 186, No. 8. pp. 2204-2219.
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