Role of Lipoproteins in Chagasic heart disease

脂蛋白在恰加斯心脏病中的作用

• 批准号: 8511513
• 负责人: Jyothi Falguni Nagajyothi
• 金额: $ 19.87万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511513
• 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 Intervention; 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.

描述（由申请人提供）：恰加斯病由细胞内寄生虫克氏锥虫引起，是一个重大公共卫生问题，对大多数拉丁美洲国家和发展中国家的移民人口具有重大社会和经济影响，每年导致数百万人死亡。恰加斯心脏病的特征是心肌炎，伴有明显的纤维化疤痕、心脏肥大、心律失常、心肌病、心力衰竭和继发性血栓栓塞。随着高脂肪“西方”饮食的改变，南美洲和中美洲最发达国家的心血管疾病死亡率正在增加。我们证明，胆固醇升高会增加克氏锥虫的入侵速度，并且这种寄生虫利用 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着增加有关。免疫荧光分析表明，受感染小鼠心肌中的寄生虫周围有低密度脂蛋白的积累。与未感染小鼠的心脏相比，感染小鼠心脏的低密度脂蛋白（LDL）、高密度脂蛋白（HDL）和总胆固醇水平显着升高。急性感染引起心肌炎、肝肿大、脂肪分解、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发挥重要作用，因为寄生虫对脂蛋白具有高亲和力，并在入侵过程中导致这些脂蛋白流入细胞。积累的脂蛋白可能会发生氧化，导致脂毒性、氧化应激、炎症和细胞死亡的发生，并在克氏锥虫感染期间导致心肌病的发生。该提案探讨了血脂、饮食与恰加斯心脏病发展之间可能的相关性，这是一个新的研究领域。了解导致慢性恰加斯心肌病的因素对于开发预防恰加斯心脏病进展的新方法至关重要。这一点尤其重要，因为恰加斯流行地区肥胖、糖尿病和血脂异常的流行有可能与这种病原体发生显着的相互作用，从而改变正常的致病过程。

项目成果

Antagonistic effect of atorvastatin on high fat diet induced survival during acute Chagas disease.

阿托伐他汀对高脂肪饮食诱导的急性恰加斯病生存的拮抗作用。

• DOI: 10.1016/j.micinf.2016.06.006
• 发表时间: 2016
• 期刊: Microbes and infection
• 影响因子: 5.8
• 作者: Zhao,Dazhi;Lizardo,Kezia;Cui,MinHui;Ambadipudi,Kamalakar;Lora,Jose;Jelicks,LindaA;Nagajyothi,JyothiF
• 通讯作者: Nagajyothi,JyothiF

Diet Modulates Adipose Tissue Oxidative Stress in a Murine Acute Chagas Model.

饮食调节小鼠急性恰加斯模型中的脂肪组织氧化应激。

• 发表时间: 2017
• 期刊: JSM atherosclerosis
• 作者: Ayyappan,JaneeshPlakkal;Nagajyothi,JyothiF
• 通讯作者: Nagajyothi,JyothiF