Role of Lipoproteins in Chagasic heart disease

脂蛋白在恰加斯心脏病中的作用

• 批准号: 8385373
• 负责人: Jyothi Falguni Nagajyothi
• 金额: $ 25.05万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385373
• 关键词: Acute; Acute Myocarditis; Adipose tissue; Adopted; Affect; Affinity; American; Antilipemic Agents; Apolipoprotein E; Apolipoproteins B; Area; Arrhythmia; Bile Acids; Binding; Binding Sites; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cells; Central America; Cessation of life; Chagas Disease; Cholesterol; Chronic; Cicatrix; Coenzyme Q10; Communicable Diseases; Country; Data; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Diagnosis; Diet; Dietary intake; Disease Progression; Dyslipidemias; Early treatment; Enzymes; Epidemic; Europe; Event; Fatty acid glycerol esters; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hepatomegaly; High Density Lipoproteins; Histology; Human; Image; Immigrant; Immigration; Immunofluorescence Immunologic; In Vitro; Infection; Inflammation; Intervention; Invaded; Investigation; LDL Cholesterol Lipoproteins; Laboratories; Latin America; Ligand Binding; Lipids; Lipolysis; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mammalian Cell; Metabolic; Methods; Mitochondria; Modality; Mus; Myocardial; Myocarditis; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; North America; Obesity; Organ; Oxidative Stress; Parasites; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Population; Probucol; Process; Public Health; Publishing; Research; Role; Sampling; Serum; Signal Pathway; Site; South America; Staging; Staining method; Stains; Stroke; Structure; Thromboembolism; Tissues; Trypanosoma cruzi; Very low density lipoprotein; animal data; atorvastatin; base; colesevelam; economic implication; heart cell; improved; inhibitor/antagonist; microsomal triglyceride transfer protein; migration; mortality; mouse model; oil red O; oxidation; oxidized low density lipoprotein; parasite invasion; pathogen; prevent; social implication

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. PUBLIC HEALTH RELEVANCE: Low Density Lipoprotein (LDL) and cholesterol play a major role in the progression of Chagasic heart disease. Chagasic heart disease is characterized by myocarditis associated with prominent fibrotic scarring, cardiac hypertrophy, arrhythmia, cardiomyopathy, heart failure and secondary thromboembolism, and is due to infection with Trypanosoma cruzi. It is a major public health problem with significant social and economic implications in Latin and South America as well as among immigrants to the USA. It is estimated to cause 50,000 deaths annually. With changes in the diet of developing countries in South and Central America there has been an epidemic of obesity, diabetes and dyslipidemia. T. cruzi utilizes LDL receptors for invasion and infection results in accumulation of LDL and cholesterol in cells/tissues, contributing to the pathogenesis of cardiomyopathy. The studies proposed in this application will significantly improve our understanding of the interaction between lipoproteins and this cardiomyopathy, which offers the best chance for early intervention strategies aimed at preventing this devastating heart disease.

描述(申请人提供)：恰加斯病是由细胞内寄生虫克氏锥虫引起的，在大多数拉丁美洲国家和发展中国家的移民人口中是一个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。慢性心脏病的特征是心肌炎伴发明显的纤维性瘢痕、心肌肥厚、心律失常、心肌病、心力衰竭和继发性血栓栓塞症。在南美洲和中美洲最发达的国家，随着人们转向高脂肪的“西方”饮食，心血管疾病的死亡率正在上升。我们证明，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。免疫荧光分析表明，在感染的小鼠心肌中，寄生虫周围的低密度脂蛋白积聚。感染小鼠心脏的低密度脂蛋白、高密度脂蛋白和总胆固醇水平明显高于未感染小鼠的心脏。急性感染导致心肌炎、肝肿大、脂肪分解、血脂水平受损以及组织/器官胆固醇升高。血清脂蛋白如低密度脂蛋白、极低密度脂蛋白和高密度脂蛋白可能在查格斯卡心脏病的进展中起主要作用，因为寄生虫对脂蛋白有很高的亲和力，并导致这些脂蛋白在入侵过程中进入细胞。在感染弓形虫的过程中，累积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，并参与心肌病的发生。这项建议探讨了血脂、饮食和查加斯病的发展之间可能的相关性，这是一个新的研究领域。了解慢性心肌病的致病因素对于开发预防慢性心肌病进展的新方法是至关重要的。这一点尤其重要，因为查加斯病区肥胖、糖尿病和血脂异常的流行有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。 公共卫生相关性：低密度脂蛋白(LDL)和胆固醇在查格西奇心脏病的进展中起主要作用。查格氏心脏病以心肌炎为特征，伴有明显的纤维化瘢痕、心肌肥大、心律失常、心肌病、心力衰竭和继发性血栓栓塞症，是由克氏锥虫感染引起的。这是一个重大的公共卫生问题，在拉丁美洲和南美洲以及在移民到美国的移民中具有重大的社会和经济影响。据估计，每年有5万人死于此病。随着南美洲和中美洲发展中国家饮食的变化，肥胖、糖尿病和血脂异常的流行。克鲁兹毛滴虫利用低密度脂蛋白受体进行侵袭和感染，导致低密度脂蛋白和胆固醇在细胞/组织中积聚，从而导致心肌病的发病。本申请中提出的研究将显著提高我们对脂蛋白和这种心肌病之间相互作用的理解，这为旨在预防这种毁灭性心脏病的早期干预策略提供了最好的机会。