期刊
CIRCULATION RESEARCH
卷 110, 期 4, 页码 598-U224出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.111.258285
关键词
hyperinsulinemia; hyperamylinemia; diabetic cardiomyopathy; calcium; HIP rat; UCD-T2DM rat
资金
- American Heart Association [BGIA2220165]
- National Science Foundation [CBET 1133339]
- National Institutes of Health [RO1-HL109501, RO1-HL089847, RO1-AG017022, RO1-HL077281, RO1-HL079071, HL075675, HL091333, AT003645, DK087307, HL107256, RO1-HL073162, RO1-HL061483, P01-HL080101]
- University of California, Office of the President
- University of California-Davis Health System
Rationale: Hyperamylinemia is common in patients with obesity and insulin resistance, coincides with hyperinsulinemia, and results in amyloid deposition. Amylin amyloids are generally considered a pancreatic disorder in type 2 diabetes. However, elevated circulating levels of amylin may also lead to amylin accumulation and proteotoxicity in peripheral organs, including the heart. Objective: To test whether amylin accumulates in the heart of obese and type 2 diabetic patients and to uncover the effects of amylin accumulation on cardiac morphology and function. Methods and Results: We compared amylin deposition in failing and nonfailing hearts from lean, obese, and type 2 diabetic humans using immunohistochemistry and Western blots. We found significant accumulation of large amylin oligomers, fibrils, and plaques in failing hearts from obese and diabetic patients but not in normal hearts and failing hearts from lean, nondiabetic humans. Small amylin oligomers were even elevated in nonfailing hearts from overweight/obese patients, suggesting an early state of accumulation. Using a rat model of hyperamylinemia transgenic for human amylin, we observed that amylin oligomers attach to the sarcolemma, leading to myocyte Ca2+ dysregulation, pathological myocyte remodeling, and diastolic dysfunction, starting from prediabetes. In contrast, prediabetic rats expressing the same level of wild-type rat amylin, a nonamyloidogenic isoform, exhibited normal heart structure and function. Conclusions: Hyperamylinemia promotes amylin deposition in the heart, causing alterations of cardiac myocyte structure and function. We propose that detection and disruption of cardiac amylin buildup may be both a predictor of heart dysfunction and a novel therapeutic strategy in diabetic cardiomyopathy. (Circ Res. 2012;110:598-608.)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据