Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury

Abstract

The myocardium generates inflammatory mediators during ischemia-reperfusion (I/R), and these mediators contribute to cardiac functional depression and apoptosis. The great majority of these data have been derived from male animals and humans. Sex has a profound effect over many inflammatory responses; however, it is unknown whether sex affects the cardiac inflammatory response to acute myocardial I/R. We hypothesized the existence of inherent sex differences in myocardial function, expression of inflammatory cytokines, and activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway after I/R. Isolated rat hearts from age-matched adult males and females were perfused (Langendorff), and myocardial contractile function was continuously recorded. After I/R, myocardium was assessed for expression of TNF-alpha, IL-1beta, and IL-6 (RT-PCR, ELISA); IL-1alpha and IL-10 mRNA (RT-PCR); and activation of p38 MAPK (Western blot). All indexes of postischemic myocardial function [left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal positive (+dP/dt) and negative (-dP/dt) values of the first derivative of pressure] were significantly improved in females compared with males. Compared with males, females had decreased myocardial TNF-alpha, IL-1beta, and IL-6 (mRNA, protein) and decreased activation of p38 MAPK pathway. These data demonstrate that hearts from age-matched adult females are relatively protected against I/R injury, possibly due to a diminished inflammatory response.

Postischemic Infusion of 17-β-Estradiol Protects Myocardial Function and Viability

“…Similarly, in animal studies, proestrus females demonstrate increased myocardial protection from I/R injury (4,5), and improved systolic and diastolic function after ischemia (6) compared to males. Female animals also exhibit decreased left ventriclular remodeling after ischemic injury (7,8), possibly due to decreased levels of inflammatory cytokines such as tumor necrosis factor α (TNF), interleukin (IL)-6, and IL-1β (9)(10)(11)(12).…”

Promoter methylation of Egr-1 site contributes to fetal hypoxia-mediated PKCε gene repression in the developing heart

“…It has been reported that gender differences exist in susceptibility to and mortality from a variety of cardiovascular diseases (20). Recent studies in animal models and cardiomyocytes further showed that female hearts had greater resistance to ischemia and reperfusion-mediated injury (30,33). Besides the possible roles of sex steroid hormones, sexspecific molecular cell death pathways, sex-specific myocardial inflammatory response, and differences between genetically male (XX) and female (XY) cells (14,30,33), the underlying mechanisms of the sex-different susceptibility to cardiovascular diseases is far less clear.…”

“…Recent studies in animal models and cardiomyocytes further showed that female hearts had greater resistance to ischemia and reperfusion-mediated injury (30,33). Besides the possible roles of sex steroid hormones, sexspecific molecular cell death pathways, sex-specific myocardial inflammatory response, and differences between genetically male (XX) and female (XY) cells (14,30,33), the underlying mechanisms of the sex-different susceptibility to cardiovascular diseases is far less clear. Indirect evidence including the reduced risk of cardiovascular diseases in premenopausal women and in postmenopausal women with estrogen replacement therapy pointed to the protective effect of estrogen in the heart (27).…”

122. Both Endogenous and Exogenous Testosterone Decrease Myocardial STAT3 Activation and SOCS3 Expression Following Acute Ischemia and Reperfusion

“…Clinically, men have higher overall incidence of heart failure, more progression to heart failure, worse age-matched cardiac contractility than women, and worse preservation of myocardial mass as they age 17 . Experimentally, animal studies have indicated that male hearts are more sensitive to acute I/R injury as exhibited by worse myocardial functional recovery, higher proinflammatory cytokine production and increased apoptotic signaling following I/R 3,4 . Although overwhelming data have established the protective effects of estrogen in females, testosterone is also an important sex hormone, which may lead to deleterious effects seen in the male heart subjected to acute injury.…”