Acute arsenic (As(III)) exposure has been reported to cause cardiac toxicity, however this toxicity was never linked to the disturbance in cytochrome P450 (P450)-mediated arachidonic acid metabolism. Therefore, we investigated the effect of acute As(III) toxicity on the expression of P450 and soluble epoxide hydrolase (sEH) and their associated arachidonic acid metabolism in mice hearts. As(III) toxicity was induced by a single intraperitoneal injection of 12.5 mg/kg of As(III). Our results showed that As(III) treatment caused a significant induction of the cardiac hypertrophic markers in addition to Cyp1b1, Cyp2b, Cyp2c, Cyp4f, and sEH gene expression in mice hearts. Furthermore, As(III) increased sEH protein expression and activity in hearts with a consequent decrease in 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) formation. Whereas the formation of 8,9-, 11,12-, 14,15-dihydroxyeicosatrienoic acids (DHETs) was significantly increased. As(III) also increased sEH mRNA and protein expression levels in addition to the hypertrophic markers which was reversed by knockdown of sEH in H9c2 cells. In conclusion, acute As(III) toxicity alters the expression of several P450s and sEH enzymes with a consequent decrease in the cardioprotective EETs which may represent a novel mechanism by which As(III) causes progressive cardiotoxicity. Furthermore, inhibiting sEH might represent a novel therapeutic approach to prevent As(III)-induced hypertrophy.
Bibliographical noteFunding Information:
This work was supported by Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant RGPIN 250139 to A.O.S. A.A-M. is the recipient of Alberta Innovates Technology Futures Scholarship, and Izaak Walton Killam memorial graduate scholarship. A.A.E. is the recipient of Egyptian Government Scholarship. S.H.K is the recipient of Alberta Innovates Health Solutions summer studentship. H.N.A is the recipient of Salman Bin Abdulaziz University scholarship, Saudi Arabia. B.N.M.Z. is the recipient of Alberta Innovates Health Solutions Scholarship.
- Arachidonic acid metabolism
- Cardiac hypertrophy
- Cytochrome P450s
- Dihydroxyeicosatrienoic acids
- Epoxyeicosatrienoic acids
- Soluble epoxide hydrolase