The molecular mechanism of cardiomyocyte protection against LPS-induced heart failure-From the regulation of cytokine signaling

心肌细胞保护脂多糖诱发心力衰竭的分子机制——从细胞因子信号传导的调控

• 批准号: 22791758
• 负责人: FUTAMATA Nobuyoshi
• 金额: $ 2.5万
• 依托单位: Kurume University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22791758/
• 关键词: 敗血症; 心不全; JAK/STAT; SOCS3; ミトコンドリア; 酸化ストレ; STAT3; 酸化ストレス

Lipopolysaccharide(LPS) was injected intraperitoneally in Balb/c and cardiac-specific SOCS3 knockout mice(SOCS3-CKO). SOCS3-CKO mice showed greater survival rate than WT mice after LPS injection. Left ventricular ejection fraction(LVEF) was restored to the baseline in SOCS3-CKO mice after LPS injection. DHE positive cells in cardiomyocytes were reduced in SOCS-CKO mice. The duration and intensity of STAT3 phosphorylation after LPS injection was greater in SOCS3-CKO mice than WT mice. Bcl-xL expression was increased and cleaved caspase3 expression and cytochrome c release were decreased in SOCS3-CKO mice. SOCS3-CKO mice prevents the depletion of Oxphos complexesIandIIIafter LPS injection. We found that expressions of multiple antioxidants genes including superoxide dismutases, catalase, glutathione peroxidase, thioredoxin reductase, peroxide thioredoxin were markedly upregulated in SOCS3-KO hearts after LPS injection. Our data show that the deletion of SOCS3 in cardiomyocytes prevents the LPS-induced LV dysfunction in mice via augmenting the STAT3 signaling and stabilizing mitochondria.

在Balb/c和心脏特异性SOCS 3敲除小鼠（SOCS 3-CKO）中腹腔内注射脂多糖（LPS）。SOCS 3-CKO小鼠在LPS注射后显示出比WT小鼠更高的存活率。在注射LPS后，SOCS 3-CKO小鼠的左心室射血分数（LVEF）恢复至基线。SOCS-CKO小鼠心肌细胞DHE阳性细胞减少。LPS注射后，SOCS 3-CKO小鼠中STAT 3磷酸化的持续时间和强度大于WT小鼠。在SOCS 3-CKO小鼠中，Bcl-xL表达增加，切割的caspase 3表达和细胞色素c释放减少。SOCS 3-CKO小鼠在LPS注射后防止Oxphos复合物I和III的消耗。结果发现，SOCS 3-KO心肌细胞在注射LPS后，超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶、硫氧还蛋白还原酶、过氧化物硫氧还蛋白等多种抗氧化基因的表达均显著上调。我们的数据表明，心肌细胞中SOCS 3的缺失通过增强STAT 3信号传导和稳定线粒体来防止LPS诱导的小鼠LV功能障碍。