Harvey Brianna I, Yoniles Arris M, Monsivais Andrea, Du Jiayue, Zadorozny Lauren, Yu Qing, Wang Meijing
Center for Surgical Sciences, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Division of Cardiothoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Int J Mol Sci. 2025 Jun 21;26(13):5963. doi: 10.3390/ijms26135963.
Cardiac dysfunction is a severe complication of sepsis that significantly increases mortality in affected patients. Previous studies have shown better myocardial responses with preserved cardiac function in female animals compared to males following lipopolysaccharide (LPS)-induced sepsis. Our published findings have revealed that females exhibited less cardiac dysfunction than males when exposed to equivalent doses of tumor necrosis factor (TNF)α, which is markedly elevated in both heart tissue and serum following LPS. These raise the question of whether the observed sex differences in LPS-induced myocardial dysfunction are a direct effect of LPS or a secondary consequence mediated by inflammatory cytokines, like TNFα. In this study, we aimed to uncover sex differences in LPS-caused direct effects on cardiac function. To do so, isolated hearts from aged-matched adult male and female mice were subjected to LPS infusion using a Langendorff method. Left ventricular developed pressure (LVDP) was continuously recorded. The female estrous cycle was determined via vaginal smear. The oxidative phosphorylation (OXPHOS) pathway and estrogen receptors (ERs) were determined in heart tissue using Western blot. We found that males exhibited worse LV function than females following the infusion of LPS at 5.0 mg/kg body weight. However, no significant differences in cardiac function and expression of ERs were observed between female groups at different estrous stages. Interestingly, LV function returned to baseline after the initial depression of LVDP during the rapid response to LPS and then depressed again following the 50 min LPS infusion. Protein levels of OXPHOS were altered differently between male and female hearts after 50 min LPS infusion. Our data demonstrate that male hearts exhibit higher sensitivity to LPS-induced rapid cardiac dysfunction compared to females, although estrogen may have a minimal influence on LPS-induced rapid functional depression. Sex differences may exist in myocardial mitochondrial responses to direct LPS insult via the OXPHOS pathway.
心脏功能障碍是脓毒症的一种严重并发症，会显著增加受影响患者的死亡率。先前的研究表明，在脂多糖（LPS）诱导的脓毒症后，雌性动物的心脏功能相较于雄性动物能更好地维持，心肌反应也更佳。我们已发表的研究结果显示，当暴露于等量的肿瘤坏死因子（TNF）α时，雌性动物的心脏功能障碍比雄性动物更少，而在LPS作用后，心脏组织和血清中的TNFα水平均会显著升高。这就引发了一个问题，即观察到的LPS诱导的心肌功能障碍中的性别差异，是LPS的直接作用，还是由炎症细胞因子（如TNFα）介导的继发后果。在本研究中，我们旨在揭示LPS对心脏功能的直接影响中存在的性别差异。为此，我们采用Langendorff方法，对年龄匹配的成年雄性和雌性小鼠的离体心脏进行LPS灌注。持续记录左心室舒张末压（LVDP）。通过阴道涂片确定雌性动物的发情周期。使用蛋白质免疫印迹法测定心脏组织中的氧化磷酸化（OXPHOS）途径和雌激素受体（ERs）。我们发现，在输注5.0 mg/kg体重的LPS后，雄性动物的左心室功能比雌性动物更差。然而，处于不同发情阶段的雌性动物组之间，心脏功能和ERs表达并未观察到显著差异。有趣的是，在对LPS的快速反应过程中，LVDP最初下降后，左心室功能恢复到基线水平，然后在输注LPS 50分钟后再次下降。LPS灌注50分钟后，雄性和雌性心脏中OXPHOS的蛋白质水平变化不同。我们的数据表明，与雌性动物相比，雄性心脏对LPS诱导的快速心脏功能障碍更为敏感，尽管雌激素可能对LPS诱导的快速功能抑制影响极小。心肌线粒体对LPS通过OXPHOS途径的直接损伤的反应可能存在性别差异。
