Altered Hepatic Gene Expression Profiles Associated With Myocardial Ischemia
Altered Hepatic Gene Expression Profiles Associated With Myocardial Ischemia
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DOI：
10.1161/circgenetics.108.795484
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发表时间：
2010-02-01
影响因子：
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通讯作者：
Takamura, Masayuki
中科院分区：
文献类型：
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作者：
Ootsuji, Hiroshi;Honda, Masao;Takamura, Masayuki
背景：急性冠状动脉综合征有时伴有凝血加速、脂质代谢和炎症反应，这些不是单独归因于心脏事件。我们假设肝脏在急性冠状动脉综合征的病理生理中起着关键作用。我们同时分析了小鼠急性心肌缺血时肝脏和心脏的基因表达谱。方法与结果：将小鼠分为假手术组、缺血再灌注组和心肌梗死组。肝缺血/再灌注小鼠作为附加对照。24小时后观察到肝脏基因表达的明显变化，尽管肝脏没有组织学变化。在心肌缺血/再灌注或梗死小鼠的肝脏中，与组织重塑、粘附分子和形态发生相关的基因显著上调，而在肝脏缺血/再灌注小鼠中则无显著上调。心肌缺血，而不是血液动力学状态的改变，被认为会显著改变肝脏基因的表达。此外，对信号通路的详细分析表明，存在干预心脏和肝脏之间的体液因子。为了解决这些问题，我们使用分离的原代肝细胞，并表明从心脏释放的骨桥蛋白实际上改变了原代肝细胞的信号通路，与心肌缺血小鼠肝脏中观察到的信号通路相同。此外，骨桥蛋白刺激原代肝细胞分泌血管内皮生长因子- a，这对组织重塑很重要。结论：心肌缺血时肝脏基因表达可能受到心脏体液因子的调控。这些结果为急性冠状动脉综合征的病理生理学提供了新的见解。（中国心血管病杂志，2010;3:68-77）
Background-Acute coronary syndrome is sometimes accompanied by accelerated coagulability, lipid metabolism, and inflammatory responses, which are not attributable to the cardiac events alone. We hypothesized that the liver plays a pivotal role in the pathophysiology of acute coronary syndrome. We simultaneously analyzed the gene expression profiles of the liver and heart during acute myocardial ischemia in mice.Methods and Results-Mice were divided into 3 treatment groups: sham operation, ischemia/reperfusion, and myocardial infarction. Mice with liver ischemia/reperfusion were included as additional controls. Marked changes in hepatic gene expression were observed after 24 hours, despite the lack of histological changes in the liver. Genes related to tissue remodeling, adhesion molecules, and morphogenesis were significantly upregulated in the livers of mice with myocardial ischemia/reperfusion or infarction but not in those with liver ischemia/reperfusion. Myocardial ischemia, but not changes in the hemodynamic state, was postulated to significantly alter hepatic gene expression. Moreover, detailed analysis of the signaling pathway suggested the presence of humoral factors that intervened between the heart and liver. To address these points, we used isolated primary hepatocytes and showed that osteopontin released from the heart actually altered the signaling pathways of primary hepatocytes to those observed in the livers of mice under myocardial ischemia. Moreover, osteopontin stimulated primary hepatocytes to secrete vascular endothelial growth factor-A, which is important for tissue remodeling.Conclusions-Hepatic gene expression is potentially regulated by cardiac humoral factors under myocardial ischemia. Theseresults provide new insights into the pathophysiology of acute coronary syndrome. (Circ Cardiovasc Genet. 2010;3:68-77.)