Sex-related differences in cardiac mitochondrial response to inflammation

心脏线粒体对炎症反应的性别相关差异

• 批准号: 10586991
• 负责人: Meijing Wang
• 金额: $ 42.73万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-22 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586991
• 关键词: Ablation; Acute; Attention; Binding; Cardiac; Cardiac Myoblasts; Cardiac Myocytes; Cardiac ablation; Cardiomyopathies; Cardiovascular system; Caveolae; Clinical; Communication; Connexin 43; Data; Disparity; Doxycycline; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exposure to; Female; Functional disorder; Goals; Health; Heart; Heart Mitochondria; Hormones; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intervention; Ischemia; Knockout Mice; Knowledge; Link; Lipopolysaccharides; Mediating; Mitochondria; Modeling; Mus; Myoblasts; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Organelles; Outcome; Peptides; Performance; Phosphorylation; Protein Isoforms; Receptor Activation; Receptors, Tumor Necrosis Factor, Type II; Recovery; Reperfusion Therapy; Resistance; Role; Sepsis; Severities; Sex Differences; Signal Transduction; Stress; Structural Protein; TNFRSF1B gene; Testing; Therapeutic; Trauma; Work; caveolin-3; cecal ligation puncture; cytokine; effective intervention; engineered exosomes; exosome; heart damage; heart function; heart preservation; improved; insight; knock-down; male; mitochondrial dysfunction; novel; novel strategies; patient prognosis; preservation; prevent; receptor; resilience; response; septic; sex; sex disparity; sexual dimorphism; therapeutic target

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.

败血症，创伤和缺血后发生心脏损伤。这些伤害触发的急性炎症 损害线粒体，这是心脏损伤严重程度的关键决定因素。性二态性影响 这些伤害的后果，没有有关性别特异性线粒体反应的信息 急性炎症。我们已经观察到TNFA急性抑制心脏功能，女性心脏是 对TNFA诱导的心脏功能障碍的抗性。我们还发现线粒体性能的性别差异 在暴露于TNFA或LPS的心肌细胞中。因此，我们认为性别特异性的线粒体反应 炎症是心脏损伤性别差异的潜在机制。线粒体连接蛋白43 （CX43）和小窝蛋白3（CAV3，一种结构蛋白，用于小窝形成必不可少的结构蛋白）参与了线粒体 缺血性心脏的保护。迄今 性别依赖性线粒体对炎症的弹性。我们最近的研究表明MitoCX43及其 较小的同工型GJA1-20K，在与性别相关的线粒体反应和雌激素介导的心脏中发挥作用 急性缺血/再灌注后的保护。我们的初步工作进一步指出：1）更好的心脏 功能与较高水平的MitoCX43磷酸化（P-CX43），MitogJA1-20K和Mitocav3有关 女性心而不是在TNFA或LPS挑战之后的男性心脏。 2）女性心肌细胞更好 线粒体性能比雄性在TNFA或LPS暴露时的表现； 3）CX43或CAV3损坏的敲低 受TNFA或LPS的成肌细胞中的线粒体功能； 4）17b-雌二醇（E2）治疗改善 线粒体功能具有增加的P-CX43和MitogJA1-20K；烧蚀心脏CX43废除E2精选的 暴露于TNFA的心肌细胞中的线粒体保护； 5）E2增强了CX43和CAV3与 雌激素受体（ER）A并促进心脏线粒体中的CX43-CAV3相互作用。我们假设这一点 女性心脏线粒体对通过ER激活抗急性炎症诱导的损伤具有抗性 与男性相比，线粒体GJA1-20K，P-CX43和CX43-CAV3相互作用。在此提议中 研究，我们将采用LPS或Cecal结扎穿刺（CLP）诱导的败血症模型来探索 MitoCX43和MitoCAV3在调节性别特异性心脏线粒体保护方面。我们将确定角色 CX43（AIM 1），CAV3及其相互作用（AIM 2）维持心脏健康和性别 急性炎症时线粒体弹性的差异；并评估GJA1-的治疗潜力 LPS或CLP诱导的化粪池心肌病中的20K外泌体（AIM 3）。我们期望这种新颖的方法 使用工程外泌体专门将GJA1-20K传递到心肌细胞将改善线粒体 化粪池心肌病中的保存和心脏功能。拟议研究的完成将带来新颖 关于性别特异性差分线粒体对急性炎症的见解，并提供 在两性中，开发了治疗急性炎症引起的急性炎症的心肌病的新方法。