Role of Ryanodine Receptors in Diabetic Cadiomyopathy

细胞内Ca ~（2+）循环紊乱是心肌收缩力下降的主要原因。 1型糖尿病（T1 D）个体和所有T1 D动物模型。其中一种蛋白质 这种缺陷是2型ryanodine受体（RyR 2），即Ca 2+离开肌浆的通道 网状组织以影响收缩。迄今为止，RyR 2功能障碍的精确分子机制 在T1 D期间，仍然未知。我们的实验室最近发现，来自链脲佐菌素的功能失调的RyR 2 （STZ）诱导的糖尿病大鼠心脏含有羰基加合物的选择碱性残基。治疗糖尿病 吡哆胺对糖尿病引起的代谢功能障碍有抑制作用， RyR 2，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， RyR 2上的加合物，恢复心室肌细胞的兴奋-收缩偶联， 导致心肌收缩力降低。这些新数据表明羰基加合物的形成 长寿命RyR 2的羰基化在功能上是重要的，而不是糖尿病的附带现象。我们 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，和（ii）确定分子机制， 吡哆胺治疗和运动训练减弱T1 D期间的RyR 2功能障碍。数据从该 该项目将提供有价值的机制的见解，如何这组研究不足的细胞氧化剂 （反应性羰基物质）损害RyR 2的活性，导致有缺陷的兴奋-收缩偶联 并降低T1 D期间的心肌收缩力。由于蛋白质的羰基应激和羰基化也 发生在2型糖尿病和代谢综合征，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个体的心肌功能障碍时， 好. 简单总结：心力衰竭是糖尿病患者发病和死亡的主要原因。但 这种心力衰竭的原因还不完全清楚。本项目旨在加深我们对以下问题的理解： 为什么糖尿病患者的心脏会衰竭这项研究尤其重要，因为它可以帮助 开发更新的治疗策略/选择，以改善糖尿病患者的生活质量， 控制糖尿病护理不断上升的经济成本，估计超过1320亿美元 每年。

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.