title: Sexually dimorphic adaptation of cardiac function: roles of epoxyeicosatrienoic acid and peroxisome proliferator-activated receptors.
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 PPARα expression, but comparable expression of eNOS, PPARβ, 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 PPARα.
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York Department of GI Surgery, Renji Hospital, School of Medicine Shanghai Jiaotong University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York.
authors.forename: Yicong
authors.initials: Y
authors.lastname: Le
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York.
authors.forename: Ghezal
authors.initials: G
authors.lastname: Froogh
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York.
authors.forename: Sharath
authors.initials: S
authors.lastname: Kandhi
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York.
authors.forename: Houli
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of GI Surgery, Shanghai Ninth People's Hospital, School of Medicine Shanghai Jiaotong University, Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York.
authors.forename: Dong
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Physiology, New York Medical College, Valhalla, New York an_huang@nymc.edu.
authors.forename: An
authors.initials: A
authors.lastname: Huang
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism*; D000222:Adaptation, Physiological; D000818:Animals; D003326:Coronary Circulation; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000502:physiology*; D008297:Male; D051379:Mice; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D047492:Peroxisome Proliferator-Activated Receptors; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; D015126:8,11,14-Eicosatrienoic Acid
keywords: Cardiac contractility; epoxyeicosatrienoic acids; peroxisome proliferator‐activated receptors; sex; soluble epoxide hydrolase