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: 8596185
• 负责人: Florin Despa
• 金额: $ 34.51万
• 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/8596185
• 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(申请人提供)：胰岛β细胞分泌胰淀素增加(高淀粉血症)在肥胖和胰岛素抵抗患者中很常见，与高胰岛素血症相吻合，并促进有毒淀粉素寡聚体的形成。低聚胰淀素诱导β细胞凋亡，从而导致2型糖尿病的发生。最近的研究表明，胰淀素低聚体也会影响血管系统、肾脏和心脏。我们的数据显示，肥胖和T2D患者衰竭的心脏中有大量低聚胰淀素的沉积，但对照组的心脏中没有。在心肌细胞损伤区域发现了低聚胰淀素，提示其在损伤机制中起作用。事实上，我们在一种“人源化”的高淀粉血症大鼠模型(HIP大鼠)上的初步研究表明，淀粉蛋白寡聚体附着在心肌细胞上，诱导氧化应激和钙调节失调，导致舒张期功能障碍和肥大。初步研究还表明，具有抗聚集特性的内源性分子，如纤溶酶和环氧二十烷醇，可以限制心脏淀粉素的积累及其肌病反应。基于这些初步结果，我们的研究计划将检验以下假设：1)低聚胰淀素在心脏中的积聚通过诱导肌膜损伤和氧化应激而加速糖尿病心脏损伤，以及2)限制心脏中胰淀素的沉积可以减少/延缓糖尿病心力衰竭的发生。这些假说将通过使用过度表达淀粉样蛋白基因的转基因大鼠模型(HIP大鼠)或非淀粉样蛋白亚型的大鼠胰淀素亚型(UCD大鼠)进行机械评估。具体地说，计划中的研究将确定寡聚化胰淀素在髋部大鼠心脏中的积聚如何a)扰乱肌膜过程，b)诱导氧化应激和心肌细胞钙离子失调，以及c)激活钙离子介导的CaMKII-HDAC和Cacineurin-NFAT肥大信号通路。根据我们的初步研究结果，髋部大鼠的心功能障碍预计甚至在糖尿病前期也会出现，就像在人类中经常观察到的那样。相反，我们的初步研究预测，年龄和血糖匹配的UCD大鼠，但缺乏心脏淀粉素沉积，可能会在糖尿病发作后显示出心功能障碍的迹象。我们的研究还将确定是否扰乱低聚胰淀素在心脏中的沉积和恢复肌膜完整性是否改善髋部大鼠模型的心功能。这一创新概念将在使用膜密封剂和循环淀粉低聚物清除剂的纵向研究中进行探索。因此，我们的研究项目提出，胰淀素的积聚是糖尿病心脏损伤多因素发病机制的关键因素，减轻胰淀素低聚物的积聚可以延缓糖尿病心力衰竭的发生。如果我们的心脏毒性胰淀素低聚物假说得到证实，那么循环低聚胰淀素是减少糖尿病心脏损伤的可行治疗靶点。