Peroxisome proliferator-activated receptor-γ activation prevents sepsis-related cardiac dysfunction and mortality in mice.
Peroxisome proliferator-activated receptor-γ activation prevents sepsis-related cardiac dysfunction and mortality in mice.
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DOI：
10.1161/circheartfailure.112.000177
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发表时间：
2013-05
期刊：
影响因子：
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通讯作者：
Goldberg IJ
中科院分区：
文献类型：
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作者：
Drosatos K;Khan RS;Trent CM;Jiang H;Son NH;Blaner WS;Homma S;Schulze PC;Goldberg IJ
败血症的心功能障碍与炎症和脂肪酸氧化减少有关（FAO）。我们假设能量剥夺可以解释败血症相关的心功能障碍。大肠杆菌脂多糖（LPS）对C57BL/6小鼠（WT）诱导心功能障碍，并在6-8h内降低过氧化物酶体增殖物激活受体(PPAR) α及其下游靶点的FAO和mRNA水平。在α肌球蛋白重链启动子（αMHC-PPARγ）驱动心肌细胞特异性表达的转基因小鼠中，lps诱导的心功能障碍受到保护。在lps处理的αMHC-PPARγ小鼠心脏中，尽管PPARα减少，但FAO和相关基因并未减少。然而，LPS处理继续诱导α mhc - ppar小鼠心脏中的炎症相关基因，如白细胞介素(IL)-1α、IL-1β、IL-6和肿瘤坏死因子α。用脂多糖和PPARγ激动剂罗格列酮治疗WT小鼠，而不使用PPARα激动剂（WY-14643），增加了粮农组织，阻止了脂多糖介导的线粒体减少，治疗了心功能障碍，尽管心脏炎症标志物的表达持续增加，但它提高了生存率。lps处理小鼠的PPARγ激活可以防止心功能障碍和死亡，尽管心脏炎症和PPARα下调。
Cardiac dysfunction with sepsis is associated with both inflammation and reduced fatty acid oxidation (FAO). We hypothesized that energy deprivation accounts for sepsis-related cardiac dysfunction. E. coli lipopolysaccharide (LPS) administered to C57BL/6 mice (WT) induced cardiac dysfunction and reduced FAO and mRNA levels of peroxisome proliferator-activated receptor (PPAR) α and its downstream targets within 6-8h. Transgenic mice in which cardiomyocyte-specific expression of PPARγ is driven by the alpha myosin heavy chain promoter (αMHC-PPARγ) were protected from LPS-induced cardiac dysfunction. Despite a reduction in PPARα, FAO and associated genes were not decreased in hearts of LPS-treated αMHC-PPARγ mice. LPS treatment, however, continued to induce inflammation-related genes, such as interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α in hearts of αMHC-PPARγ mice. Treatment of WT mice with LPS and the PPARγ agonist rosiglitazone, but not the PPARα agonist (WY-14643), increased FAO, prevented LPS-mediated reduction of mitochondria and treated cardiac dysfunction, as well as it improved survival despite continued increases in the expression of cardiac inflammatory markers. Activation of PPARγ in LPS-treated mice prevented cardiac dysfunction and mortality despite development of cardiac inflammation and PPARα downregulation.