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Prevention of Angiotensin II‐ Induced Aortic Aneurysm And Associated Pathogenesis By Inhibiting CYP1B1 Or Its Gene Disruption ( ApoE ‐/‐ /Cyp1b1 ‐/‐ Mice)
Author(s) -
Thirunavukkarasu Shyamala,
Khan Nayaab,
Jennings Brett,
Malik Kafait
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.418.2
Subject(s) - cyp1b1 , oxidative stress , apolipoprotein e , angiotensin ii , chemistry , inflammation , endocrinology , medicine , receptor , cytochrome p450 , disease , metabolism
This study addressed the role of CYP1B1 in AngII‐induced aortic aneurysms (AA). ApoE ‐/‐ /Cyp1b1 +/+ mice were bred with Cyp1b1 ‐/‐ mice to generate ApoE ‐/‐ /Cyp1b1 ‐/‐ (DKO) mice. ApoE ‐/‐ /Cyp1b1 +/+ and DKO mice were administered Ang II (700 ng/min/kg) or vehicle for 1 month. One group of Ang II treated mice were administered CYP1B1 inhibitor 2, 3′, 4, 5′‐tetramethoxystilbene (TMS) (300 mg/kg/i.p) or its vehicle (DMSO). Histological and ultrasound analysis showed that Ang II infusion produced AA in ApoE ‐/‐ /Cyp1b1 +/+ mice that was prevented by TMS or Cyp1b1 gene disruptionAngII induced AA lesions had increased infiltration of platelets, macrophages, T cells and enhanced extracellular matrix degradation. Increased MMP2, 9, platelet derived growth factor (PDGF)‐D, COX 2, reactive oxygen species and absence of PAI‐1 were observed in the AA lesions in ApoE ‐/‐ /Cyp1b1 +/+ mice. This was minimized by treatment with TMS or Cyp1b1 gene disruption. QT‐PCR studies indicated downregulation of markers of inflammation and oxidative stress including, P‐selectin, Itgα11, PDGFrB, MMP 2, 9&12 in aortas of DKO mice receiving AngII. This suggests that the pathological changes in AngII‐induced AA are mediated by CYP1B1 via increased oxidative stress. Therefore CYP1B1 could serve as a novel target for the treatment of AA.