Role of Lipoproteins in Chagasic heart disease

描述（由申请人提供）：恰加斯病是由细胞内寄生虫克氏锥虫引起的，是在大多数拉丁美洲国家和发展中国家移民人口中具有重大社会和经济影响的重大公共卫生问题，每年造成数百万人死亡。恰加斯心脏病的特点是心肌炎伴显著的纤维化瘢痕、心肌肥厚、心律失常、心肌病、心力衰竭和继发性血栓栓塞。在南美洲和中美洲最发达国家，由于改用高脂肪的“西方”饮食，心血管疾病的死亡率正在上升。我们证明了升高的胆固醇增加了克氏锥虫的入侵率，这种寄生虫利用LDLr入侵宿主细胞。寄生虫入侵与心脏和肝脏等器官中低密度脂蛋白水平的显著增加有关。免疫荧光分析显示，感染小鼠心肌中寄生虫周围有LDL的积累。与未感染小鼠相比，感染小鼠心脏的LDL、HDL和总胆固醇水平显著升高。急性感染引起心肌炎、肝肿大、脂解、血脂水平受损和组织/器官胆固醇升高。血清脂蛋白如LDL、极低密度脂蛋白（VLDL）和HDL可能在恰加斯心脏病的进展中起主要作用，因为寄生虫对脂蛋白具有高亲和力，并在侵袭期间导致这些脂蛋白涌入细胞。积累的脂蛋白可能发生氧化，导致脂毒性、氧化应激、炎症和细胞死亡，并有助于克氏t感染期间心肌病的发展。本研究旨在探讨血脂、饮食与恰加斯心脏病发展之间的关系，这是一个新的研究领域。了解导致慢性恰加斯型心肌病的因素对于开发预防恰加斯型心脏病进展的新方法至关重要。这一点尤其重要，因为恰加斯病流行地区的肥胖、糖尿病和血脂异常流行可能与这种病原体发生重大相互作用，从而改变正常的致病过程。

DESCRIPTION (provided by applicant): Chagas disease, caused by an intracellular parasite Trypanosoma cruzi, is a major public health problem with significant social and economic implications in most Latin American countries and among immigrant populations in developing countries, and is responsible for millions of deaths annually. Chagasic heart disease is characterized by myocarditis associated with prominent fibrotic scarring, cardiac hypertrophy, arrhythmia, cardiomyopathy, heart failure and secondary thromboembolism. Mortality due to cardiovascular disease is increasing in the most developed countries of South and Central America with the change to a high fat "western" diet. 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 liver. Immunofluorescence analysis demonstrated an accumulation of LDL around parasites in the myocardium of infected mice. LDL, HDL and total cholesterol levels of hearts of infected mice were significantly increased compared to the hearts of uninfected mice. Acute infection caused myocarditis, hepatomegaly, lipolysis, impaired serum lipid levels, and elevated tissue/organ cholesterol. Serum lipoproteins such as LDL, very Low Density Lipoprotein (VLDL) and HDL likely play a major role in the progression of Chagasic heart disease as parasites have high affinity for lipoproteins and causes influx of these lipoproteins into cells during invasion. The accumulated lipoproteins may undergo oxidation and responsible for the development of lipotoxicity, oxidative stress, inflammation and cell death, and contribute to the development of cardiomyopathy during T. cruzi infection. This proposal explores the possible correlation between serum lipids, diet and the development of Chagasic heart disease which is a new area of investigation. Understanding the factors responsible for chronic Chagasic cardiomyopathy is critical in order to develop new methods to prevent the progression of Chagasic heart disease. This is especially important as the epidemic of obesity, diabetes and dyslipidemia in Chagas endemic regions has the potential for significant interactions with this pathogen, thus altering th normal pathogenic process.