BACKGROUND: Chronic hypersecretion of the pancreatic hormone amylin is common in humans with obesity or prediabetic insulin resistance and induces amylin aggregation and proteotoxicity in the pancreas. We recently showed that hyperamylinemia also affects the cardiovascular system. Here, we investigated whether amylin aggregates interact directly with cardiac myocytes and whether controlling hyperamylinemia protects the heart.
METHODS AND RESULTS: By Western blot, we found abundant amylin aggregates in lysates of cardiac myocytes from obese patients, but not in controls. Aggregated amylin was elevated in failing hearts, suggesting a role in myocyte injury. Using rats overexpressing human amylin in the pancreas (HIP rats) and control myocytes incubated with human amylin, we show that amylin aggregation at the sarcolemma induces oxidative stress and Ca2+ dysregulation. In time, HIP rats developed cardiac hypertrophy and left-ventricular dilation. We then tested whether metabolites with antiaggregation properties, such as eicosanoid acids, limit myocardial amylin deposition. Rats were treated with an inhibitor of soluble epoxide hydrolase, the enzyme that degrades endogenous eicosanoids. Treatment doubled the blood concentration of eicosanoids, which drastically reduced incorporation of aggregated amylin in cardiac myocytes and blood cells, without affecting pancreatic amylin secretion. Animals in the treated group showed reduced cardiac hypertrophy and left-ventricular dilation. The cardioprotective mechanisms included the mitigation of amylin-induced cardiac oxidative stress and Ca2+ dysregulation.
CONCLUSIONS: The results suggest blood amylin as a novel therapeutic target in diabetic heart disease and elevating blood levels of antiaggregation metabolites as a pharmacological strategy to reduce amylin aggregation and amylin-mediated cardiotoxicity.
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Work was supported by NIH (1R01-HL118474-01A1 to F. Despa; R01-HL109501 to S. Despa; R01-HL85844 and R01-HL85727 to Chiamvimonvat; 5R01-HL061483 to Taegtmeyer; R01-HL089847 and R01-HL105993 to Margulies; R01-ES002710, P42-ES004699 and U24-DK097154 to Hammock), AHA (13GRNT16470034 to F. Despa), ADA (1-13-IN-70 to F. Despa), and NSF (CBET 1133339 to F. Despa). Hammock is a George and Judy Marcus Senior Fellow of the American Asthma Foundation. Harris is supported by NIH T32 Training Grant in Basic and Translational Cardiovascular Science (T32-HL86350).
Despa, Sanda; Sharma, Savita; Harris, Todd R.; Dong, Hua; Li, Ning; Chiamvimonvat, Nipavan; Taegtmeyer, Heinrich; Margulies, Kenneth B.; Hammock, Bruce D.; and Despa, Florin, "Cardioprotection by Controlling Hyperamylinemia in a "Humanized" Diabetic Rat Model" (2014). Pharmacology and Nutritional Sciences Faculty Publications. 33.