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细胞胰淀素分泌增加（高胰淀素血症）在肥胖和胰岛素抵抗患者中很常见，与高胰岛素血症同时发生，并促进有毒胰岛淀粉样多肽寡聚体的形成。寡聚胰淀素诱导 β 细胞凋亡，导致 2 型糖尿病的发生。最近的研究表明胰岛淀粉样多肽寡聚物也会影响血管系统、肾脏和心脏。我们的数据显示，肥胖和 T2D 患者衰竭的心脏中存在大量寡聚胰淀素沉积，但对照组的心脏中则没有。在心肌细胞损伤区域发现了寡聚胰淀素，表明其在损伤机制中发挥作用。事实上，我们对高胰淀素血症“人源化”大鼠模型（HIP 大鼠）的初步研究表明，胰淀素寡聚物附着在心肌细胞上，诱导氧化应激和 Ca2+ 失调，导致舒张功能障碍和肥厚。该初步研究还表明，具有抗聚集特性的内源性分子，例如纤溶酶和环氧类二十烷酸，可以限制胰淀素的心脏积累及其肌病反应。基于这些初步结果，我们的研究计划将检验以下假设：1) 寡聚胰淀素在心脏中的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，2) 限制心脏中的胰淀素沉积可能会减少/延缓糖尿病的发作心脏衰竭。这些假设将通过使用过度表达淀粉样变性人胰岛淀粉样多肽（HIP 大鼠）或非淀粉样变性大鼠胰岛淀粉样多肽（UCD 大鼠）的转基因大鼠模型进行机械评估。具体来说，计划中的研究将确定低聚胰淀素在 HIP 大鼠心脏中的积累如何 a) 扰乱肌膜过程，b) 诱导氧化应激和肌细胞 Ca2+ 失调，以及 c) 激活 Ca2+ 介导的 CaMKII-HDAC 和钙调神经磷酸酶-NFAT 肥大信号通路。根据我们的初步研究结果，HIP 大鼠的心脏功能障碍预计甚至在糖尿病前期也会出现，正如在人类中经常观察到的那样。相比之下，我们的初步研究预测，年龄和血糖匹配但缺乏心脏淀粉样蛋白沉积的UCD大鼠可能在糖尿病发作后表现出心脏功能障碍的迹象。我们的研究还将确定破坏低聚胰淀素在心脏中的沉积并恢复肌膜完整性是否可以改善 HIP 大鼠模型的心脏功能。这一创新概念将在使用膜密封剂和循环胰淀素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，胰岛淀粉样多肽的积累是糖尿病性心脏损伤的多因素发病机制的关键因素，减轻胰岛淀粉样多肽寡聚体的积累可能会延缓糖尿病性心力衰竭的发作。如果我们的心脏毒性胰岛淀粉样多肽寡聚物的假设得到证实，那么循环胰岛淀粉样多肽寡聚物是减少糖尿病性心脏损伤的可行治疗靶点。