Hyperamylinemia in Diabetic Heart Disease: Mechanisms, Responses, and Prevention

糖尿病性心脏病中的高淀粉样蛋白血症：机制、反应和预防

• 批准号: 8725228
• 负责人: Florin Despa
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-23 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725228
• 关键词: Adjuvant; Affect; Age; Apoptosis; Area; Beta Cell; Binding; Blood; Calcineurin; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cell membrane; Cells; Data; Deposition; Development; Diabetes Mellitus; Diagnosis; Epidemic; Excretory function; Figs - dietary; Functional disorder; Glucose; Heart; Heart Diseases; Heart Hypertrophy; Heart Injuries; Heart failure; Histone Deacetylase; Hormones; Human; Hyperinsulinism; Hypertrophy; Injury; Insulin; Insulin Resistance; Ion Channel; Ions; Kidney; Left; Lipid Peroxidation; Longitudinal Studies; Mediating; Membrane; Membrane Potentials; Metabolic syndrome; Mitochondria; Modeling; Muscle Cells; Myocardial; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oligonucleotides; Onset of illness; Oxidative Stress; Pancreas; Pathogenesis; Pathway interactions; Patients; Pilot Projects; Plasmin; Poloxamer; Poloxamers; Prediabetes syndrome; Prevention; Process; Production; Property; Protein Isoforms; Rattus; Research; Research Project Grants; Research Proposals; Risk; Role; Sarcolemma; Signal Pathway; Solubility; Structure; Structure of beta Cell of islet; System; Testing; Therapeutic; Tissues; Transgenic Organisms; Vascular System; Ventricular; base; calmodulin-dependent protein kinase II; catalyst; diabetic; high risk; improved; in vivo; inhibitor/antagonist; innovation; islet amyloid polypeptide; overexpression; public health relevance; response; therapeutic target; tool

DESCRIPTION (provided by applicant): Increased secretion of amylin by pancreatic beta-cells (hyperamylinemia) is common in obese and insulin resistant patients, coincides with hyperinsulinemia, and promotes formation of toxic amylin oligomers. Oligomeric amylin induces beta-cell apoptosis contributing to the development of type-2 diabetes. Recent studies demonstrate that amylin oligomers also affect the vascular system, kidneys, and heart. Our data show large deposits of oligomerized amylin in failing hearts from obese and T2D patients, but not in hearts from controls. Oligomeric amylin was found in myocyte injury areas suggesting a role in the mechanism of injury. Indeed, our pilot study on a "humanized" rat model of hyperamylinemia (the HIP rat) indicates that amylin oligomers attach to cardiac myocytes and induce oxidative stress and Ca2+ dysregulation leading to diastolic dysfunction and hypertrophy. The pilot study also suggests that endogenous molecules with anti-aggregation properties, such as plasmin and epoxyeicosanoids, limit cardiac accumulation of amylin and its myopathic response. Based on these preliminary results, our research proposal will test the hypotheses that 1) cardiac accumulation of oligomerized amylin accelerates diabetic heart injury by inducing sarcolemmal damage and oxidative stress, and 2) limiting amylin deposition in the heart may reduce/ delay the onset of diabetic heart failure. These hypotheses will mechanistically be assessed by using transgenic rat models overexpressing either the amyloido- genic human amylin (HIP rats) or the non-amyloidogenic rat amylin isoform (UCD rats). Specifically, planned studies will determine how accumulation of oligomerized amylin in the HIP rat heart a) disrupts sarcolemmal processes, b) induces oxidative stress and myocyte Ca2+ dysregulation, and c) activates Ca2+-mediated CaMKII-HDAC and calcineurin-NFAT hypertrophy signaling pathways. Based on the results of our pilot study, cardiac dysfunction in HIP rats is expected to develop even in pre-diabetes, as often observed in humans. In contrast, our pilot study predicts that UCD rats matched for age and glucose, but lacking cardiac amylin deposition, may show signs of cardiac dysfunction after the onset of diabetes. Our research will also determine if disrupting deposition of oligomeric amylin in the heart and recovering sarcolemmal integrity improve cardiac function in the HIP rat model. This innovative concept will be explored in longitudinal studies using membrane sealants and scavengers of circulating amylin oligomers. Hence, our research project proposes that amylin buildup is a key contributor to the multifactorial pathogenesis of diabetic heart injury and that mitigating amylin oligomer accumulation could delay the onset of diabetic heart failure. If our hypothesis of cardiotoxic amylin oligomer is proven, then circulating amylin oligomers are a feasible therapeutic target to reduce diabetic heart injury.

描述（由申请人提供）：胰腺β-细胞（高氨基血症）对淀粉纤维的分泌增加在肥胖和胰岛素抵抗患者中很常见，与高胰岛素血症重合，并促进毒性淀粉蛋白酶寡聚的形成。寡聚链淀粉蛋白诱导β细胞凋亡，导致2型糖尿病的发展。最近的研究表明，淀粉蛋白酶低聚物也会影响血管系统，肾脏和心脏。我们的数据表明，肥胖和T2D患者的心脏失败的寡聚淀粉蛋白的大量沉积物，而不是对照组的心脏。在肌细胞损伤区域发现了寡聚淀粉蛋白，这表明在损伤机理中起作用。实际上，我们对高氨基血症“人源化”大鼠模型（髋关节）的试点研究表明，淀粉蛋白酶低聚物附着于心肌细胞上，并诱导氧化应激以及CA2+功能障碍，导致舒张功能障碍和肥大。试点研究还表明，具有抗凝聚特性的内源性分子，例如纤溶酶和环氧酸的，限制了链淀粉的心脏积累及其肌病反应。基于这些初步结果，我们的研究提案将检验以下假设：1）寡聚淀粉蛋白的心脏积累通过诱导肌膜损伤和氧化应激加速糖尿病性心脏损伤，以及2）在心脏中限制淀粉蛋白酶沉积可能会减少糖尿病性心脏衰竭的发作/延迟糖尿病性心脏失败的发作。这些假设将通过使用过表达淀粉样蛋白基因淀粉蛋白（髋关节大鼠）或非淀粉样蛋白生成大鼠淀粉蛋白链淀粉蛋白（UCD大鼠）的转基因大鼠模型来进行机械评估。具体而言，计划的研究将确定髋部心脏中的寡链淀粉蛋白的积累如何a）破坏肌膜过程，b）诱导氧化应激和肌细胞CA2+失调以及c）激活Ca2+介导的CA2+介导的CAMKII-HDAC和钙氨酸-HDAC和calcineurin-NFAT-NFAT-NFAT-NFAT超前信号通道。根据我们的试点研究的结果，正如人类在人类中经常观察到的那样，髋部大鼠的心脏功能障碍甚至在糖尿病前也会发展。相比之下，我们的试点研究预测，UCD大鼠的年龄和葡萄糖匹配，但缺乏心脏淀粉纤维沉积，可能会显示糖尿病发作后心脏功能障碍的迹象。我们的研究还将确定在心脏中寡聚淀粉蛋白的沉积并恢复肌膜完整性是否会改善髋部大鼠模型中的心脏功能。这种创新的概念将在纵向研究中使用膜密封剂和循环链球菌寡聚物的清除剂进行探讨。因此，我们的研究项目提出，氨基蛋白的积累是糖尿病心脏损伤多因素发病机制的关键因素，缓解淀粉蛋白酶低聚物的积累可能会延迟糖尿病心力衰竭的开始。如果我们证明了心脏毒性淀粉蛋白低聚物的假设，则循环淀粉蛋白低聚物是减少糖尿病心脏损伤的可行治疗靶标。