Pathogenic contribution of lipid homeostasis to chagasic Cardiomyopathy

描述(由申请人提供)：由细胞内原生动物克氏锥虫引起的查加西克心肌病(CCM)是拉丁美洲流行地区死亡和发病的主要原因，估计有1500万人感染或携带该疾病。全球化增加了北美、欧洲和澳大利亚等发达国家的恰加斯病风险。我们证明，升高的胆固醇增加了克氏毛滴虫的侵袭率，这种寄生虫利用低密度脂蛋白受体来入侵宿主细胞。寄生虫的入侵与心脏和脂肪组织等器官中低密度脂蛋白水平的显著增加有关。我们的研究表明：(I)在急性感染期间，克氏支原体以脂肪组织(AT)为靶标，而脂肪组织是这种寄生虫的能量来源和储存库；(Ii)在AT急性感染中，脂肪酸显著减少，胆固醇增加，以及 重要的是显著的脂解(脂肪损失)和脂肪细胞坏死，(Iii)脂解导致急性感染期间血脂水平和寄生虫血症(血清寄生虫水平)的增加，这两者在急性感染结束时都显著下降，(Iv)在感染急性期结束时，心脏脂质水平和寄生虫负荷显著增加，(V)心肌中SREBPs和胆固醇水平的升高与感染的不确定阶段有关，(Vi)在慢性感染期间心脏胆固醇水平仍然升高 在Chagas小鼠模型中，ER和线粒体氧化应激与急性感染有关，并持续到慢性阶段。在CCM患者中观察到脂营养不良和心脏胆固醇升高。提示相互关联的AT-心脏脂质代谢在CCM的发生发展中起重要作用。然而，克鲁兹毛滴虫在感染的不同阶段改变AT-心脏脂质代谢的确切机制尚不清楚。根据这些观察结果，我们假设慢性CCM是通过两种不同的脂代谢紊乱来发展的：(1)急性感染诱导的脂解增加和脂类流入心肌；(2)不确定的(中期)感染相关的诱导心肌新生脂肪生成。总之，我们认为脂肪组织的脂解作用调节心脏脂肪沉积，而心脏脂质稳态的改变导致CCM的发生。这项建议的总体目标是研究在毛滴虫感染的不同阶段，在CCM进展过程中AT和心脏脂质代谢之间的机制联系。为了充分了解脂肪细胞和脂蛋白在人CCM发病机制中的作用，我们分别使用了转基因“脂肪-ATTAC”和双转基因“CETP-ApoB”小鼠。了解慢性CCM的致病因素将有助于开发新的方法来预防目前尚无疫苗或有效药物的Chagasic心脏病的进展。

DESCRIPTION (provided by applicant): Chagasic Cardiomyopathy (CCM) caused by the intracellular protozoan Trypanosoma cruzi is a major cause of mortality and morbidity in the endemic regions of Latin America with an estimated 15 million infected with or are carriers of the disease. Globalization has increased the risk of Chagas disease in developed countries including North America, Europe and Australia. We demonstrated that elevated cholesterol increased the rate of T. cruzi invasion and that this parasite utilizes LDLr to invade host cells. Parasite invasion was associated with a significant increase in the levels of LDL in organs such as heart and adipose tissue. Our studies reveal that : (i) T. cruzi targets adipose tissue (AT) during acute infection which acts as an energy source and reservoir for this parasite, (ii) In AT acute infection results in a significant decrease in fatty acid and an increase in cholesterol, and importantly a significant level of lipolysis (fat loss) and fat cell necrosis, (iii) Lipolysis resuts in increased serum lipid levels and parasitemia (serum parasite level) during acute stage of infection both of which significantly decrease by the end of acute infection, (iv) By the end of acute stage of infection, cardiac lipid levels and parasite load are significantly increased, (v) Elevated expression of SREBPs and cholesterol levels in the myocardium associate with the indeterminate stage of infection, (vi) Cardiac cholesterol levels are still elevated during chronic infection, and (vii) ER and mitochondrial oxidative stress is associated with acute infection and persists to chronic stage in murine chagas model. Lipodystrophy and elevated cardiac cholesterol is observed in CCM patients. This suggests that interlinked AT-cardiac lipid metabolism play a major role in the development of CCM. However, the exact mechanisms through which T. cruzi alter AT-cardiac lipid metabolism at different stages of infection is not known. Based on these observations we hypothesize that chronic CCM is developed through two distinct perturbations in lipid metabolism; (1) acute infection-induced increase in lipolysis and lipid influx to myocardium, and (2) Indeterminate (intermediate) stage infection-associated induction of de novo lipogenesis in myocardium. In short, we propose that adipose tissue lipolysis regulates cardiac lipid deposition, and the altered cardiac lipid homeostasis results in CCM. The overall goal of this proposal is to investigate the mechanistic link between AT and cardiac lipid metabolism in the progression of CCM during different stages of T. cruzi infection. In order to fully appreciate the role of adipocytes and Lipoproteins in the pathogenesis of human CCM we are using transgenic "FAT-ATTAC" and double transgenic "CETP-ApoB" mice respectively. Understanding the factors responsible for chronic CCM will aid in the development of new approaches to prevent progression of Chagasic heart disease for which currently no vaccine or effective drug available.