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Overexpression of Human Soluble Epoxide Hydrolase Exacerbates Coronary Reactive Hyperemia Reduction in
Ahmad Hanif1, Matthew L Edin2, Darryl C Zeldin2
1Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV; and.
Insights
Angiotensin-II (Ang-II) significantly worsens coronary reactive hyperemia (CRH) reduction in mice overexpressing soluble epoxide hydrolase (sEH). This finding highlights sEH as a potential therapeutic target for cardiovascular diseases.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
Background:
- Coronary reactive hyperemia (CRH) is a crucial indicator of cardiovascular health.
- Angiotensin-II (Ang-II) is known to impair CRH, particularly in cardiovascular diseases.
- The role of soluble epoxide hydrolase (sEH) in Ang-II-mediated CRH impairment remains unclear.
Purpose of the Study:
- To investigate the effect of Ang-II on CRH in wild-type (WT) versus human-sEH-overexpressed (Tie2-sEH Tr) mice.
- To determine if sEH overexpression exacerbates Ang-II-induced CRH reduction.
Main Methods:
- Utilized the Langendorff system to measure coronary blood flow in isolated mouse hearts.
- Induced 15-second ischemia followed by assessment of CRH in both WT and Tie2-sEH Tr mice.
- Administered Ang-II to assess its impact on CRH parameters, including repayment volume, duration, and peak flow.
Main Results:
- Ang-II significantly reduced CRH repayment volume, duration, and peak flow in both WT and Tie2-sEH Tr mice.
- Tie2-sEH Tr mice exhibited a more pronounced reduction in CRH parameters compared to WT mice when treated with Ang-II.
- Ang-II-AT1 receptor and CYP4A expression were elevated in Tie2-sEH Tr mice.
Conclusions:
- Ang-II exacerbates the reduction in CRH in mice overexpressing sEH.
- sEH overexpression potentiates the detrimental effects of Ang-II on coronary circulation.
- Targeting sEH may offer a therapeutic strategy to mitigate Ang-II-induced cardiovascular dysfunction.
Abstract:
Coronary reactive hyperemia (CRH) is impaired in cardiovascular diseases, and angiotensin-II (Ang-II) exacerbates it. However, it is unknown how Ang-II affects CRH in Tie2-sEH Tr (human-sEH-overexpressed) versus wild-type (WT) mice. sEH-overexpression resulted in CRH reduction in Tie2-sEH Tr versus WT. We hypothesized that Ang-II exacerbates CRH reduction in Tie2-sEH Tr versus WT. The Langendorff system measured coronary flow in Tie2-sEH Tr and WT. The hearts were exposed to 15-second ischemia, and CRH was assessed in 10 mice each. Repayment volume was reduced by 40.50% in WT treated with Ang-II versus WT (7.42 ± 0.8 to 4.49 ± 0.8 mL/g) and 48% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (5.18 ± 0.4 to 2.68 ± 0.3 mL/g). Ang-II decreased repayment duration by 50% in WT-treated with Ang-II versus WT (2.46 ± 0.5 to 1.24 ± 0.4 minutes) and 54% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (1.66 ± 0.4 to 0.76 ± 0.2 minutes). Peak repayment flow was reduced by 11.2% in WT treated with Ang-II versus WT (35.98 ± 0.7 to 32.11 ± 1.4 mL/g) and 4% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (32.18 ± 0.6 to 30.89 ± 1.5 mL/g). Furthermore, coronary flow was reduced by 43% in WT treated with Ang-II versus WT (14.2 ± 0.5 to 8.15 ± 0.8 mL/min/g) and 32% in Tie2-sEH Tr treated with Ang-II versus Tie2-sEH Tr (12.1 ± 0.8 to 8.3 ± 1.2 mL/min/g). Moreover, the Ang-II-AT 1 -receptor and CYP4A were increased in Tie2-sEHTr. Our results demonstrate that Ang-II exacerbates CRH reduction in Tie2-sEH Tr mice.
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