title: Cardioprotection by controlling hyperamylinemia in a "humanized" diabetic rat model.
abstract: 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.
  
  
  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 Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY (S.D., S.S., F.D.) Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY (S.D., F.D.).
authors.forename: Sanda
authors.initials: S
authors.lastname: Despa
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY (S.D., S.S., F.D.).
authors.forename: Savita
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Entomology, University of California, Davis, CA (T.R.H., H.D., B.D.H.).
authors.forename: Todd R
authors.initials: TR
authors.lastname: Harris
authors.affiliation: Department of Entomology, University of California, Davis, CA (T.R.H., H.D., B.D.H.).
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Internal Medicine, University of California, Davis, CA (N.L., N.C.).
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, University of California, Davis, CA (N.L., N.C.) Department of Veterans Affairs, Northern California Health Care System, Mather, CA (N.C.).
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
authors.affiliation: Department of Internal Medicine, The University of Texas School of Medicine at Houston, Houston, TX (H.T.).
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.affiliation: Cardiovascular Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (K.B.M.).
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.affiliation: Department of Entomology, University of California, Davis, CA (T.R.H., H.D., B.D.H.).
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY (S.D., S.S., F.D.) Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY (S.D., F.D.).
authors.forename: Florin
authors.initials: F
authors.lastname: Despa
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D006321:Heart / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000187:drug effects / Q000235:genetics* / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity; D018384:Oxidative Stress / Q000187:drug effects; D010179:Pancreas / Q000378:metabolism; D011236:Prediabetic State / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D012508:Sarcolemma / Q000648:ultrastructure; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C557705:1-(1-acetyl-piperidine-4-yl)-3-adamantan-1-yl-urea; D015777:Eicosanoids; D058228:Islet Amyloid Polypeptide; D014508:Urea; D004851:Epoxide Hydrolases; D000218:Adamantane; D002118:Calcium
keywords: amyloid; calcium; circulation; diabetes mellitus; heart diseases