Sex-related differences in cardiac mitochondrial response to inflammation

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Cardiac damage occurs following sepsis, trauma, and ischemia. Acute inflammation triggered by these injuries impairs mitochondria, a key determinant for the severity of cardiac damage. While sex dimorphism impacts consequences of these injuries, no information is available regarding sex-specific mitochondrial responses to acute inflammation. We have observed that TNFa acutely depresses cardiac function and female hearts are resistant to TNFa-induced cardiac dysfunction. We have also found sex differences in mitochondrial performance in cardiomyocytes exposed to TNFa or LPS. Thus, we reason that sex-specific mitochondrial responses to inflammation is the underlying mechanism for sex disparities in cardiac damage. Mitochondrial connexin-43 (Cx43) and caveolin-3 (Cav3, a structural protein essential for caveolae formation) are involved in mitochondrial protection in the ischemic heart. To date, neither mitochondrial (mito)Cx43 nor mitoCav3 has been studied for sex-dependent mitochondrial resilience to inflammation. Our recent study has suggested that mitoCx43 and its smaller isoform, Gja1-20k, play a role in sex-related mitochondrial responses and estrogen-mediated cardiac protection following acute ischemia/reperfusion. Our preliminary work has further indicated: 1) better cardiac function is associated with higher levels of mitoCx43 phosphorylation (p-Cx43), mitoGja1-20k and mitoCav3 in female hearts than in male hearts following TNFa or LPS challenge; 2) female cardiomyocytes have better mitochondrial performance than male ones upon TNFa or LPS exposure; 3) knockdown of Cx43 or Cav3 impairs mitochondrial function in myoblasts subjected to TNFa or LPS; 4) 17b-estradiol (E2) treatment improves mitochondrial function with increased p-Cx43 and mitoGja1-20k; ablation of cardiac Cx43 abolishes E2-elicited mitochondrial protection in cardiomyocytes exposed to TNFa; and 5) E2 enhances Cx43 and Cav3 binding to estrogen receptor (ER)a and promotes Cx43-Cav3 interaction in cardiac mitochondria. We hypothesize that female heart mitochondria are resistant to acute inflammation-induced damage via ER(s) activation-increased mitochondrial Gja1-20k, p-Cx43 and Cx43-Cav3 interaction in comparison to the male ones. In this proposed study, we will employ LPS- or cecal ligation puncture (CLP)-induced sepsis models to explore the role of mitoCx43 and mitoCav3 in regulating sex-specific cardiac mitochondrial protection. We will determine the roles of Cx43 (Aim 1), Cav3 and their interaction (Aim 2) in maintaining cardiac mitochondrial health and in sex differences of mitochondrial resilience upon acute inflammation; and assess the therapeutic potential of Gja1- 20k-loaded exosomes in LPS- or CLP-induced septic cardiomyopathy (Aim 3). We expect that novel approach using engineered exosomes to specifically deliver Gja1-20k to cardiomyocytes will improve mitochondrial preservation and cardiac function in septic cardiomyopathy. Completion of the proposed study will bring novel insights about sex-specific differential mitochondrial responses to acute inflammation and offer the basis of developing novel approaches in treating acute inflammation-caused cardiomyopathy in both sexes.