Sex-Based Differences in Myocardial Infarction: More Protection in Pre-Menopausal Female Mice

Abstract

Accumulating studies have shown that premenopausal females are less susceptible to adverse left ventricular (LV) remodeling following MI when compared to age-matched males with undefined mechanisms. MI prevalence, however, substantially increased with age to reach comparable level post-menopause. For example, the male to female risk ratio under the age of 45 is 10:1, while increasing significantly above the age of 75 to 1:2. Sex dimorphism in MI-induced LV remodeling is potentially attributed to the protective effects of the endogenous estrogen (17-β Estradiol). In this study, we aimed at investigating the mechanisms along with the potential involvement of estrogen in the observed sex-based differences between premenopausal female and age-matched male mice in cardiac remodeling post-MI. Five months old males and females C57BL6/J mice were employed in this study and divided into 5 groups: Male control, female control, MI-males, MI-females, and MI ovariectomized females. MI was induced by ligating the left anterior descending artery, whereas estrogen depletion was induced by bilateral ovariectomy. Mice were sacrificed 7 days post-MI. Our hemodynamic analysis revealed exacerbated adverse LV remodeling in MI mice of both sexes to the same extent in term of ejection fraction (EF), fractional shortening (FS), stroke volume (SV) and cardiac output (CO). Of note, left ventricle end systolic volume and left ventricle end diastolic volume markedly increased in MI mice of both sexes, but to a higher extent in MI males. Enhanced cardiac dysfunction post-ovariectomy however, was observed by marked decrease in EF and CO. Histologically, Hematoxylin and Eosin staining showed that unlike MI female mice, MI males exhibited enhanced cardiomyocyte hypertrophy. Molecularly, the anti-inflammatory cytokines interleukin IL-4 and IL-13 significantly decreased in MI male mice, while remained unchanged in MI female mice. A significant decrease in IL-13 levels was observed in MI female mice post-ovariectomy, only. Conversely, IL-10, an anti-inflammatory and profibrotic marker, markedly increased in MI male mice when compared the female counterparts, whereas significantly decrease in MI females post-ovariectomy. Additionally, Pp38/p38, a mitogen activated protein kinase implicated in cell survival following MI, significantly decreased in MI mice of both sexes. A further reduction in Pp38/p38 was observed in MI female mice post ovariectomy. Metabolically, total cardiac NAD levels substantially decreased in MI male mice, only. Furthermore, SIRT-3, an NAD+ dependent enzyme involved in mitochondria biogenesis, markedly decreased in MI mice of both sexes. Collectively, our findings revealed that both sexes exhibited enhanced adverse LV remodeling in 7 days post- MI, with female mice being more protected.