Abstract
Epoxyeicosatrienoic acids (EETs) are cardioprotective mediators metabolized by soluble epoxide hydrolase (sEH) to form corresponding diols (DHETs). As a sex‐susceptible target, sEH is involved in the sexually dimorphic regulation of cardiovascular function. Thus, we hypothesized that the female sex favors EET‐mediated potentiation of cardiac function via downregulation of sEH expression, followed by upregulation of peroxisome proliferator‐activated receptors (PPARs). Hearts were isolated from male (M) and female (F) wild‐type (WT) and sEH‐KO mice, and perfused with constant flow at different preloads. Basal coronary flow required to maintain the perfusion pressure at 100 mmHg was significantly greater in females than males, and sEH‐KO than WT mice. All hearts displayed a dose‐dependent decrease in coronary resistance and increase in cardiac contractility, represented as developed tension in response to increases in preload. These responses were also significantly greater in females than males, and sEH‐KO than WT. 14,15‐EEZE abolished the sex‐induced (F vs. M) and transgenic model‐dependent (KO vs. WT) differences in the cardiac contractility, confirming an EET‐driven response. Compared with M‐WT controls, F‐WT hearts expressed downregulation of sEH, associated with increased EETs and reduced DHETs, a pattern comparable to that observed in sEH‐KO hearts. Coincidentally, F‐WT and sEH‐KO hearts exhibited increased PPAR α expression, but comparable expression of eNOS, PPAR β, and EET synthases. In conclusion, female‐specific downregulation of sEH initiates an EET‐dependent adaptation of cardiac function, characterized by increased coronary flow via reduction in vascular resistance, and promotion of cardiac contractility, a response that could be further intensified by PPAR α.
Highlights
The incidence of ischemic heart diseases distributes in a sexually dimorphic manner, as evidenced by the significantly lower incidence in females than age-matched males, which is due at least in part, to the better cardiac perfusion in women (Gura 1995; Huang and Kaley 2004)
A potential gene involved in the sexual dimorphism of cardiovascular diseases is the Ephx2 that encodes for the protein of soluble epoxide hydrolase and is responsible for converting cardioprotective mediators, namely epoxyeicosatrienoic acids (EETs; members of epoxy fatty acid family), to their corresponding non- or less bioactive diols (Kersten et al 2000; Mark-Kappeler et al 2011; Harris and Hammock 2013)
Cardiac contractility in males and females exhibited different responses when the hearts were challenged with the same increase in preload, characterized as significantly greater responses in F-WT than MWT, and in F-KO than M-KO mice, respectively (Fig. 4A and B)
Summary
The incidence of ischemic heart diseases distributes in a sexually dimorphic manner, as evidenced by the significantly lower incidence in females than age-matched males, which is due at least in part, to the better cardiac perfusion in women (Gura 1995; Huang and Kaley 2004). A potential gene involved in the sexual dimorphism of cardiovascular diseases is the Ephx that encodes for the protein of soluble epoxide hydrolase (sEH) and is responsible for converting cardioprotective mediators, namely epoxyeicosatrienoic acids (EETs; members of epoxy fatty acid family), to their corresponding non- or less bioactive diols (dihydroxyeicosatrienoic acids, DHETs) (Kersten et al 2000; Mark-Kappeler et al 2011; Harris and Hammock 2013). Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society
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