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: 7635454
• 负责人: KESHORE R BIDASEE
• 金额: $ 3.41万
• 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/7635454
• 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

Pertubation of intracellular Ca 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.

细胞内钙循环紊乱是心肌收缩功能下降的主要原因 1型糖尿病(T1D)的个体和T1D的所有动物模型。其中一种蛋白质有助于 这个缺陷是2型Ryanodine受体(RyR2)，钙离子通过这个通道离开肌浆 起收缩作用的网状结构。到目前为止，RyR2功能障碍的确切分子机制 在T1D期间仍然未知。我们实验室最近发现由链脲佐菌素引起的功能障碍的RyR2 链脲佐菌素(STZ)诱导的糖尿病大鼠心脏在选定的碱性残基上含有羰基加合物。糖尿病的治疗 吡哆胺清除活性羰基可钝化糖尿病大鼠中枢神经系统功能障碍 RyR2，使心肌细胞兴奋收缩偶联和心肌收缩能力正常化。运动训练 STZ-糖尿病大鼠还减少了活性羰基的产生，减少了羰基的形成 RyR2上的加合物，恢复了心室肌细胞的兴奋-收缩偶联和钝化的糖尿病- 导致心肌收缩能力降低。这些新数据表明，羰基加合物的形成 长寿的RyR2的(羰化)在功能上是重要的，而不是糖尿病的附带现象。我们的 中心假说是“糖尿病导致RyR2上关键氨基酸残基的羰基化， 导致RyR2功能障碍、兴奋-收缩偶联障碍和心力衰竭。 利用细胞培养和STZ-糖尿病大鼠模型(I)阐明 加合物在糖尿病期间改变RyR2的功能，以及(Ii)确定通过什么分子机制 吡哆胺治疗和运动训练可减轻T1D期间RyR2功能障碍。来自于此的数据 该项目将为这组未被研究的细胞氧化剂如何 (活性羰基)削弱RyR2的活性，导致兴奋-收缩偶联缺陷 T1D时心肌收缩功能降低。因为蛋白质的羰基胁迫和羰基化也 发生在2型糖尿病和代谢综合征中，从这个项目中获得的知识也可能是有用的 在设计新的治疗策略来管理这些患者的心肌功能障碍时， 井。 综述：心力衰竭是糖尿病患者发病率和死亡率的主要原因。然而， 这种心力衰竭的原因还不完全清楚。这个项目旨在加深我们对以下问题的理解 糖尿病患者心力衰竭的原因。这项研究特别重要，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和 控制糖尿病护理不断攀升的经济成本，估计超过1320亿美元 每年一次。