Cardiovascular Medicine, Department of Medicine, Boston University Medical Center, Boston, Massachusetts.
Department of Pathology, Boston University Medical Center, Boston, Massachusetts.
Shock. 2019 Jul;52(1):52-60. doi: 10.1097/SHK.0000000000001245.
Mice challenged with lipopolysaccharide develop cardiomyopathy in a sex and redox-dependent fashion. Here we extended these studies to the cecal ligation and puncture (CLP) model.We compared male and female FVB mice (wild type, WT) and transgenic littermates overexpressing myocardial catalase (CAT). CLP induced 100% mortality within 4 days, with similar mortality rates in male and female WT and CAT mice. 24 h after CLP, isolated (Langendorff) perfused hearts showed depressed contractility in WT male mice, but not in male CAT or female WT and CAT mice. In WT male mice, CLP induced a depression of cardiomyocyte sarcomere shortening (ΔSS) and calcium transients (ΔCai), and the inhibition of the sarcoplasmic reticulum Ca ATPase (SERCA). These deficits were associated with overexpression of NADPH-dependent oxidase (NOX)-1, NOX-2, and cyclooxygenase 2 (COX-2), and were partially prevented in male CAT mice. Female WT mice showed unchanged ΔSS, ΔCai, and SERCA function after CLP. At baseline, female WT mice showed partially depressed ΔSS, ΔCai, and SERCA function, as compared with male WT mice, which were associated with NOX-1 overexpression and were prevented in CAT female mice.In conclusion, in male WT mice, septic shock induces myocardial NOX-1, NOX-2, and COX-2, and redox-dependent dysregulation of myocardial Ca transporters. Female WT mice are resistant to CLP-induced cardiomyopathy, despite increased NOX-1 and COX-2 expression, suggesting increased antioxidant capacity. Female resistance occurred in association with NOX-1 overexpression and signs of increased oxidative signaling at baseline, indicating the presence of a protective myocardial redox hormesis mechanism.
脂多糖刺激的小鼠以性别和氧化还原依赖的方式发生心肌病。在此，我们将这些研究扩展到盲肠结扎和穿刺（CLP）模型。我们比较了雄性和雌性 FVB 小鼠（野生型，WT）和过表达心肌过氧化氢酶（CAT）的转基因同窝仔鼠。CLP 在 4 天内引起 100%的死亡率，雄性和雌性 WT 和 CAT 小鼠的死亡率相似。CLP 后 24 小时，分离（Langendorff）灌流心脏显示 WT 雄性小鼠的收缩功能下降，但雄性 CAT 或雌性 WT 和 CAT 小鼠没有。在 WT 雄性小鼠中，CLP 诱导肌小节缩短（ΔSS）和钙瞬变（ΔCai）的抑制，以及肌浆网 Ca ATP 酶（SERCA）的抑制。这些缺陷与 NADPH 依赖性氧化酶（NOX）-1、NOX-2 和环氧化酶 2（COX-2）的过表达有关，并在雄性 CAT 小鼠中部分预防。雌性 WT 小鼠在 CLP 后 ΔSS、ΔCai 和 SERCA 功能没有变化。在基线时，与雄性 WT 小鼠相比，雌性 WT 小鼠的 ΔSS、ΔCai 和 SERCA 功能部分降低，这与 NOX-1 过表达有关，并在 CAT 雌性小鼠中预防。总之，在雄性 WT 小鼠中，感染性休克诱导心肌 NOX-1、NOX-2 和 COX-2 以及氧化还原依赖的心肌 Ca 转运蛋白失调。尽管雌性 WT 小鼠的 NOX-1 和 COX-2 表达增加，但对 CLP 诱导的心肌病具有抗性，这表明抗氧化能力增加。雌性抗性的发生与 NOX-1 过表达和基线时氧化信号增加的迹象有关，表明存在保护性心肌氧化还原应激机制。
