Role of caveolins in epoxyeicosatrienoic acid mediated protective effects against ischemia reperfusion injury

Abstract

Cytochrome P450 epoxygenases can metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which have known cardioprotective effects. Subsequent metabolism of EETs by soluble epoxide hydrolase (sEH) reduces the protective effect. Caveolins (Cav-1, -2, and -3) are structural proteins that insert into the plasma membrane to form caveolae, which can bind molecules important in cardiac signal transduction and function. The objective of this study was to assess the role of Cav in EET mediated cardioprotection. Hearts from sEH null (KO) and littermate control (WT) mice were perfused in Langendorff mode and subjected to 20min ischemia followed by 40min reperfusion. Immunohistochemistry, immunoblot and electron microscopy were performed to study localization of Cav and changes in ultrastructure. In WT heart, cav-1 and cav-3 were present in cardiomyocyte (CM) and capillary endothelial cell at baseline. Following ischemia, cav-1 but not cav-3 disappeared from CM; moreover, caveolae were absent in WT hearts. Mitochondria and T-tubules were swollen, and cristae of mitochondria were damaged. Improved postischemic functional recovery observed in KO or WT hearts treated with 11,12-EET corresponded with higher cav-1 expression in plasma membrane and mitochondrial fractions. Taken together, our data suggest EETs prevent the loss of cav-1, resulting in increased mitochondrial targeting and cardioprotection.