Abstract P172: Sex Differences in Obesity Associated Diastolic Dysfunction in Western Diet Fed Mice
Premenopausal women are protected against cardiovascular disease (CVD); however, this protection is lost in the setting of obesity, insulin resistance and type 2 diabetes. The mechanisms responsible for abrogation of the sex-related CVD protection are not clearly understood. We have recently developed a translational model in which female mice fed a diet high in fat and refined carbohydrates (western diet - WD) develop cardiac stiffness and diastolic dysfunction earlier than males consuming a WD. We hypothesized that these earlier adverse effects in females are mediated via increased mineralocorticoid (MR) activation/oxidative stress mediated activation (phosphorylation) of the serine kinase, S6K1 which promotes cardiac growth and fibrosis. Accordingly, four week old male and female C57BL6/J mice were fed a WD (containing high fat [46%], sucrose [17.5%], and high fructose corn syrup [17.5%]) or control diet (CD) for 8 and 16 weeks. Two-dimensional echocardiograms were used to evaluate diastolic function. Immunohistochemistry and western blotting were used to evaluate MR receptor expression and S6K1 phosphorylation. Diastolic dysfunction, indicated by prolonged isovolumic relaxation time (IVRT) and abnormal myocardial performance (increased myocardial performance index [MPI]) was present at 8 weeks in WD-fed female, but not male mice. Although male mice fed a WD exhibited diastolic dysfunction at 16 weeks, diastolic function as assessed by IVRT was more pronounced in female mice. The magnitude of cardiac fibrosis and oxidative stress was greater in females consuming a WD. Moreover, levels of plasma aldosterone, expression of MR (WD female 1.60 fold, WD male 1.26 fold), phosphorylation of S6K1 (WD females 2.92 fold, WD males 1.97 fold) and levels of mRNA for monocyte chemoattractant protein 1 (MCP-1, WD females 1.86 fold, WD males 1.16 fold) were higher in WD-fed female mice compared to WD-fed male mice. These results suggest enhanced cardiac MR mediated S6K1 activation and increased immune and inflammatory responses contribute to enhanced fibrosis and abrogation of cardiac protection in female mice fed a WD high in fat and fructose.
Author Disclosures: A. Aroor: None. J. Habibi: None. V.G. DeMarco: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Modest; Boehringer Ingelheim. G. Jia: None. M. Garro: None. C. Manrique: None. J. Sowers: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; National Institutes of Health, Veterans Affairs Merit Award.
- © 2015 by American Heart Association, Inc.