# Sex-related differences in cardiac mitochondrial response to inflammation

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $418,197

## Abstract

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 n...

## Key facts

- **NIH application ID:** 10757015
- **Project number:** 5R01HL155957-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Meijing Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,197
- **Award type:** 5
- **Project period:** 2022-12-22 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757015

## Citation

> US National Institutes of Health, RePORTER application 10757015, Sex-related differences in cardiac mitochondrial response to inflammation (5R01HL155957-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757015. Licensed CC0.

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