Effect of EET-A treatment on Cardiac Hypertrophy Induced by Isoproterenol in Sprague-Dawley Rats.

Authors

Sara A Helal, Samar H Gerges, Keshav Gopal, John R Falck, John R Ussher, Ayman O S El-Kadi

Published in

Journal of cardiovascular pharmacology. Jun 04, 2026. Epub Jun 04, 2026.

Abstract

Metabolites of arachidonic acid (AA) generated by cytochrome P450 (CYP) enzymes play significant roles in cardiac pathophysiology. Epoxyeicosatrienoic acids (EETs) exert vasodilatory, anti-inflammatory, and cardioprotective effects, but their rapid degradation limits therapeutic use. A metabolically stable analog, EET-A, was developed to mimic native 14,15-EET. The role of EET-A in cardiac hypertrophy and its interaction with CYP pathways remains unclear. This study investigated whether EET-A modulates cardiac hypertrophy, CYP enzyme expression, and AA metabolite formation in an isoproterenol (ISO)-induced model. Male Sprague-Dawley rats were administered ISO (1 mg/kg/day, i.p.) for 7 consecutive days to induce cardiac hypertrophy, with EET-A (10 mg/kg, i.p.) administered in parallel. Cardiac hypertrophy induction was confirmed, and the gene and protein levels of expression of cardiac CYP enzymes were assessed. Hydroxyeicosatetraenoic acids (HETEs) and EETs formation rates were measured using liquid chromatography-mass spectrometric analysis after incubating heart microsomes with AA. Concurrent administration of EET-A with ISO attenuated cardiac hypertrophy, as evidenced by reduced heart weight/body weight, heart weight/tibial length ratio and the gene expression of β-myosin heavy chain compared with ISO alone. ISO significantly increased cardiac hypertrophic markers and altered CYP-mediated AA metabolism, including increased CYP1B1 expression, elevated mid-chain HETEs, and reduced EET formation rates. EET-A partially prevented these changes by suppressing CYP1B1 protein induction, decreasing 11-HETE formation, and restoring 8,9-EET levels. These findings indicate that EET-A attenuates ISO-induced cardiac hypertrophy and partially modulates CYP-dependent AA metabolism, conferring partial protection against β-adrenergic receptor agonist-induced cardiac remodeling.

PMID:
42359609
Bibliographic data and abstract were imported from PubMed on 26 Jun 2026.

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