Cardioprotection by controlling hyperamylinemia in a "humanized" diabetic rat model.
Cardioprotection by controlling hyperamylinemia in a "humanized" diabetic rat model.
复制标题
通过控制“人性化”糖尿病大鼠模型中的高氨基血症的心脏保护。
DOI：
10.1161/jaha.114.001015
复制
发表时间：
2014-08-21
影响因子：
5.4
通讯作者：
Despa F
中科院分区：
文献类型：
--
作者：
Despa S;Sharma S;Harris TR;Dong H;Li N;Chiamvimonvat N;Taegtmeyer H;Margulies KB;Hammock BD;Despa F
胰腺激素胰淀素的慢性高分泌在肥胖或糖尿病前期胰岛素抵抗的人群中很常见，并诱导胰淀素聚集和胰腺中的蛋白质毒性。我们最近发现高淀粉酶血症也会影响心血管系统。在这里，我们研究了胰淀素聚集体是否直接与心肌细胞相互作用，以及控制高胰淀素血症是否保护心脏。通过Western blot，我们发现肥胖患者心肌细胞的裂解物中有丰富的胰淀素聚集体，但在对照组中没有。聚集的胰淀素在衰竭的心脏中升高，提示其在心肌细胞损伤中起作用。通过在胰腺中过度表达人胰淀素的大鼠（HIP大鼠）和用人胰淀素孵育的对照肌细胞，我们发现肌膜上的胰淀素聚集诱导氧化应激和Ca2+失调。随着时间的推移，HIP大鼠出现心肌肥厚和左室扩张。然后，我们测试了具有抗聚集特性的代谢物，如类二十烷酸，是否限制心肌淀粉酶沉积。用可溶性环氧化物水解酶抑制剂治疗大鼠，这种酶能降解内源性二十烷类化合物。治疗使血液中类二十烷酸浓度增加一倍，从而大大减少心肌细胞和血细胞中聚集的胰淀素的掺入，而不影响胰淀素的分泌。治疗组的动物表现出心肌肥厚和左室扩张的减轻。心脏保护机制包括减轻胰淀素诱导的心脏氧化应激和Ca2+失调。结果表明，血液中胰淀素是糖尿病心脏病的一个新的治疗靶点，提高血液中抗聚集代谢物的水平是一种减少胰淀素聚集和胰淀素介导的心脏毒性的药理策略。
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. 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. 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.