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Endothelial Overexpression of Human Cytochrome P450 Epoxygenase 2J2 Protects from Angiotensin II‐induced Negative Modulation of Coronary Reactive Hyperemia
Author(s) -
Hanif Ahmad,
Zeldin Darryl C,
Nayeem Mohammed A
Publication year - 2016
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.30.1_supplement.lb531
Subject(s) - epoxygenase , medicine , endocrinology , chemistry , angiotensin ii , reactive hyperemia , endothelial dysfunction , ischemia , cytochrome p450 , arachidonic acid , endothelium , vasodilation , receptor , metabolism , biochemistry , enzyme
Coronary reactive hyperemia (CRH) is an indirect measure of coronary reserve, and its impairment is associated with cardiovascular disease. Angiotensin II (Ang II) has powerful effects on many organs including coronary endothelium. In the vascular system, Ang II acts as a potent vasoconstrictor and produces endothelial dysfunction and smooth muscle proliferation. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia / reperfusion injury. Cytochrome P450 epoxygenase 2J2 is involved in EETs generation from arachidonic acid. EETs level is increased in mice with increased endothelial of CYP2J2 (Tie2‐CYP2J2 Tr). Our previous data showed that CRH is increased in Tie2‐CYP2J2 Tr whereas CRH is decreased by Ang II. We hypothesized that endothelial overexpression of human cytochrome P450 epoxygenase 2J2 protects from Ang II‐induced negative modulation of CRH. Coronary flow (CF) in isolated Tie2‐CYP2J2 Tr and C57BL6J mice (WT) mouse heart was measured using Langendorff system. Perfused isolated heart was exposed to 15 second ischemia and CRH was assessed. Following ischemia, flow repayment volume [RV, the area under the curve normalized to heart weight (ml/g)] was significantly increased (57%) in Tie2‐CYP2J2 Tr vs. WT mice (11.3 ± 1.3 vs. 7.2 ± 0.5, p<0.05, Fig. 1). When Ang II (1nM) was perfused, RV was significantly reduced by 45% in WT treated with Ang II (1nM) vs. WT (7.2 ± 0.5 to 4.0 ± 0.4, p<0.05) and by 42% in Tie2‐CYP2J2 Tr treated with Ang II vs. Tie2‐CYP2J2 Tr (11.3 ± 1.3 to 6.6 ± 0.9, p<0.05, Fig. 1). But, the RV was significantly increased (67%) in Tie2‐CYP2J2 Tr treated with Ang II vs. WT treated with Ang II (p<0.05, Fig. 1). Ang II also decreased repayment duration (min) by 48% in WT treated with Ang II (1nM) vs. WT (2.5 ± 0.3 to 1.3 ± 0.2, p<0.05) and by 37% in Tie2‐CYP2J2 Tr treated with Ang II vs. Tie2‐CYP2J2 Tr (3.3 ± 0.4 to 2.1 ± 0.4, p<0.05, Fig. 2) whereas, repayment duration was significantly increased (62%) in Tie2‐CYP2J2 Tr treated with Ang II vs. WT treated with Ang II (p<0.05, Fig. 2). Moreover Ang II decreased baseline coronary flow (ml/min/g) by 28% in WT treated with Ang II (1nM) vs. WT (13.2 ± 1.2 to 9.5 ± 1.3, p<0.05) and by 22% in Tie2‐CYP2J2 Tr treated with Ang II vs. Tie2‐CYP2J2 Tr (13.8 ± 1.3 to 10.7 ± 1.4, p<0.05, Fig. 3). Heart Rate and left ventricular pressure (LVP) were not different between the groups. Our results demonstrate that Ang II reduces CRH in both WT and Tie2‐CYP2J2 Tr, compared to their respective controls. However, Ang II effect is more pronounced in WT (45%, p<0.05). At the same time, CRH is increased (67%) Tie2‐CYP2J2 Tr treated with Ang II vs. WT treated with Ang II (p<0.05), and no change has been observed in Tie2‐CYP2J2 Tr treated with Ang II vs. WT (p>0.05). These data suggest that Ang II‐induced negative effect on myocardial recovery from ischemic insult may be protected by over‐expression of endothelial CYP2J2 (Tie2‐CYP2J2 Tr). Support or Funding Information Supported by HL‐114559 to MAN and z01‐ES025034 to DCZ. 123