Enhanced Expression of Plasminogen Activator Inhibitor May Prevent Cardiac Rupture in Female and Castrated Mice After Myocardial Infarction

Objective: The objective of this study was to test the hypothesis that gender has a significant impact on cardiac inflammation, fibrosis, and survival after myocardial infarction (MI) in a murine model of left coronary artery ligation (CAL) by investigating the underlying cellular-molecular mechanisms. Methods: Age-matched male and female mice were randomly assigned into 6 groups: sham-operated males, sham-operated females, intact males with CAL, intact females with CAL, castrated males with CAL, and oophorectomized females with CAL. The animals were sacrificed 14 days postoperatively. The hearts from each group were harvested for morphologic studies (n = 6) (infarct and fibrotic area, inflammatory cell markers CD40 and CD68) and mRNA expression analyses (n = 6) of pro- and antiinflammatory molecules, including matrix metalloproteinase (MMP)-9, plasminogen activator inhibitor (PAI)-1, interleukin (IL)-10, transforming growth factor (TGF)-beta, and endothelial nitric oxide synthase (eNOS). Results: Intact males with CAL had significantly lower 14-day survival compared with intact females with CAL. Similarly, the infarct areas in intact males with CAL were largest compared with other CAL animals. The fibrotic area was also larger in intact males with CAL than in intact females with CAL. Numbers of CD40(+)/CD68(+) cells and MMP-9 expression were higher in intact males with CAL than in intact females with CAL and castrated males with CAL. IL-10, eNOS, and TGF-beta were significantly suppressed in oophorectomized females with CAL compared with intact females with CAL. Intact females with CAL and castrated males with CAL exhibited notably enhanced post-MI PAT-1 expression. Conclusions: Male gender (compared with female) may be an unfavorable prognostic factor after MI in terms of enhanced inflammation and fibrosis in a murine model. Although castration seemed to be significantly antiinflammatory and antifibrotic after MI, oophorectomy had no significant impact on survival, suggesting that factors other than estrogen may account for favorable outcome after MI in the female gender. Furthermore, enhanced postinfarct PAT-1 expression in castrated and female mice may contribute to suppressed MMP-9 expression and survival advantage. (Gend Med. 2011;8:239-251) (C) 2011 Elsevier HS Journals, Inc. All rights reserved.