Role of Ryanodine Receptors in Diabetic Cadiomyopathy

兰尼定受体在糖尿病心肌病中的作用

• 批准号: 7345434
• 负责人: KESHORE R BIDASEE
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7345434
• 关键词: Address; Adhesions; Adolescent; Adult; Amines; Amino Acids; Animal Model; Animals; Arginine; Arrhythmia; Attenuated; Binding; Biological Assay; Blood Vessels; Ca(2+)-Transporting ATPase; Caffeine; Calcium; Calmodulin; Cardiac; Caring; Cells; Charge; Child; Complex; Condition; Confocal Microscopy; Contracts; Coupling; Cultured Cells; Cyclic ADP-Ribose; Data; Defect; Depressed mood; Development; Diabetes Mellitus; Dissociation; Echocardiography; Economics; Enzymes; Epidemic; Etiology; Exercise; Exhibits; FKBP1B gene; Frequencies; Functional disorder; Glutamine; Heart; Heart failure; Histidine; Impairment; In Vitro; Incubated; Individual; Insulin-Dependent Diabetes Mellitus; Knowledge; Laboratories; Left; Life; Ligands; Lysine; M-Mode Echocardiography; Mass Spectrum Analysis; Measurement; Measures; Mediating; Membrane; Metabolic syndrome; MgATP; Modeling; Molecular; Morbidity - disease rate; Muscle Cells; Mutation; Myocardial; Myocardial dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Other Finding; Oxidants; Patients; Phosphorylation; Physiologic intraventricular pressure; Plasma; Probability; Production; Proteins; Pyridoxamine; Pyruvaldehyde; Quality of life; Rate; Rattus; Recombinants; Research; Research Personnel; Role; RyR2; Ryanodine; Ryanodine Receptor Calcium Release Channel; SERCA2a; Sarcoplasmic Reticulum; Semicarbazides; Site; Site-Directed Mutagenesis; Streptozocin; Stress; Syndrome; Testing; Text; Therapeutic; Time; Tissues; Training; Ventricular; Western Blotting; Work; adduct; amine oxidase; carbamylhydrazine; cost; design; diabetic; diabetic cardiomyopathy; diabetic rat; hemodynamics; improved; in vivo; insight; mortality; mutant; novel therapeutics; programs; prototype; response; stem; sudden cardiac death; type I and type II diabetes

DESCRIPTION (provided by applicant): Perturbation of intracellular Ca2+ cycling is a primary cause for the depressed myocardial contractility in individuals with type 1 diabetes (T1D) and in all animal models of T1D. One of the proteins that contribute to this defect is type 2 ryanodine receptor (RyR2), the channel through which Ca2+ leave the sarcoplasmic reticulum to effect contraction. To date, precise molecular mechanisms responsible for RyR2 dysfunction during T1D remain unknown. Our laboratory recently found that dysfunctional RyR2 from streptozotocin (STZ)-induced diabetic rat hearts contain carbonyl adducts on select basic residues. Treatment of diabetic rats with pyridoxamine to scavenge reactive carbonyl species blunted diabetes-induced dysfunction of RyR2, normalize myocyte excitation-contraction coupling and myocardial contractility. Exercise training STZ-diabetic rats also reduced production of reactive carbonyl species, decreased formation of carbonyl adducts on RyR2, restored excitation-contract coupling in ventricular myocytes and blunted diabetes- induced reduction in myocardial contractility. These new data suggest that formation of carbonyl adducts (carbonylation) of long-lived RyR2 is functionally important and not an epiphenomenon of diabetes. Our central hypothesis is "diabetes leads to carbonylation of critical amino acid residues on RyR2, causing RyR2 dysfunction, impairment of excitation-contraction coupling and heart failure." We will use cell culture and STZ-diabetic rat models to (i) elucidate molecular mechanisms by which carbonyl adducts alter RyR2 function during diabetes, and (ii) determine molecular mechanisms by which pyridoxamine treatment and exercise training attenuate RyR2 dysfunction during T1D. Data from this project will provide valuable mechanistic insights into how this group of understudied cellular oxidants (reactive carbonyl species) impairs the activity of RyR2, leading to defective excitation-contraction coupling and reduced myocardial contractility during T1D. Since carbonyl stress and carbonylation of proteins also occurs in type 2 diabetes and metabolic syndrome, knowledge gained from this project could also be useful in designing newer therapeutic strategies for management of myocardial dysfunction in these individuals as well. Lay summary: Heart failure is a primary cause of morbidity and mortality in diabetic patients. However, the cause of this heart failure is not fully understood. This project is designed to further our understanding as to why the heart fails in individuals with diabetes. This research is especially important since it could help in the development of newer therapeutic strategies/options to improve the quality of life of diabetic patients and control the escalating economic cost of diabetes care, which is estimated to be in excess of $132 billion annually.

描述（由申请方提供）：细胞内Ca 2+循环的扰动是1型糖尿病（T1 D）个体和所有T1 D动物模型中心肌收缩力降低的主要原因。导致这种缺陷的蛋白质之一是2型ryanodine受体（RyR 2），这是Ca 2+离开肌浆网以实现收缩的通道。迄今为止，T1 D期间RyR 2功能障碍的确切分子机制仍不清楚。我们的实验室最近发现，从链脲佐菌素（STZ）诱导的糖尿病大鼠心脏功能障碍的RyR 2含有羰基加合物上选择的基本残基。用吡哆胺治疗糖尿病大鼠以抑制反应性羰基物质减弱糖尿病诱导的RyR 2功能障碍，使心肌细胞兴奋-收缩偶联和心肌收缩性正常化。运动训练STZ-糖尿病大鼠还减少了反应性羰基物质的产生，减少了RyR 2上羰基加合物的形成，恢复了心室肌细胞中的兴奋-收缩偶联，并减弱了糖尿病诱导的心肌收缩性降低。这些新数据表明，长寿命RyR 2的羰基加合物（羰基化）的形成在功能上很重要，而不是糖尿病的附带现象。我们的中心假设是“糖尿病导致RyR 2上关键氨基酸残基的羰基化，导致RyR 2功能障碍，兴奋-收缩偶联受损和心力衰竭。“我们将使用细胞培养和STZ糖尿病大鼠模型来（i）阐明羰基加合物在糖尿病期间改变RyR 2功能的分子机制，以及（ii）确定吡哆胺治疗和运动训练在T1 D期间减弱RyR 2功能障碍的分子机制。该项目的数据将提供有价值的机制见解，了解这组未充分研究的细胞氧化剂（活性羰基物质）如何损害RyR 2的活性，导致T1 D期间有缺陷的兴奋-收缩偶联和心肌收缩力降低。由于羰基应激和蛋白质羰基化也发生在2型糖尿病和代谢综合征中，因此从该项目中获得的知识也可用于设计用于管理这些个体的心肌功能障碍的更新治疗策略。 简单总结：心力衰竭是糖尿病患者发病和死亡的主要原因。然而，这种心力衰竭的原因还不完全清楚。该项目旨在进一步了解糖尿病患者心脏衰竭的原因。这项研究尤其重要，因为它可以帮助开发新的治疗策略/选择，以改善糖尿病患者的生活质量，并控制糖尿病护理不断上升的经济成本，估计每年超过1320亿美元。