{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T02:32:38Z","timestamp":1788834758930,"version":"build-2803163510"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2014,8,15]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              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 (\n              <jats:styled-content style=\"fixed-case\">HIP<\/jats:styled-content>\n              rats) and control myocytes incubated with human amylin, we show that amylin aggregation at the sarcolemma induces oxidative stress and Ca\n              <jats:sup>2+<\/jats:sup>\n              dysregulation. In time,\n              <jats:styled-content style=\"fixed-case\">HIP<\/jats:styled-content>\n              rats developed cardiac hypertrophy and left\u2010ventricular 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\u2010ventricular dilation. The cardioprotective mechanisms included the mitigation of amylin\u2010induced cardiac oxidative stress and Ca\n              <jats:sup>2+<\/jats:sup>\n              dysregulation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">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\u2010mediated cardiotoxicity.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.114.001015","type":"journal-article","created":{"date-parts":[[2014,8,22]],"date-time":"2014-08-22T04:29:49Z","timestamp":1408681789000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["Cardioprotection by Controlling Hyperamylinemia in a \u201cHumanized\u201d Diabetic Rat Model"],"prefix":"10.1161","volume":"3","author":[{"given":"Sanda","family":"Despa","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY"},{"name":"Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savita","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd R.","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Entomology, University of California, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Entomology, University of California, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of California, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nipavan","family":"Chiamvimonvat","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of California, Davis, CA"},{"name":"Department of Veterans Affairs, Northern California Health Care System, Mather, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinrich","family":"Taegtmeyer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The University of Texas School of Medicine at Houston, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth B.","family":"Margulies","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"Hammock","sequence":"additional","affiliation":[{"name":"Department of Entomology, University of California, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florin","family":"Despa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY"},{"name":"Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.68.040104.124723"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2009.476"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1015328625394"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-006-0022-y"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-010-9131-7"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000012466.50373.E8"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1097\/HCO.0b013e3282fcc2fa"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.258285"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5002305"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00042.2009"},{"key":"e_1_3_3_12_2","first-page":"245","article-title":"Impaired glucose tolerance is associated with increased islet amyloid polypeptide (IAPP) immunoreactivity in pancreatic beta cells","volume":"135","author":"Johnson KH","year":"1989","unstructured":"Johnson KH, O'Brien TD, Jordan K, Westermark P. 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