Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents
Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents
复制标题
DOI：
10.1172/jci40096
复制
发表时间：
2010-05-01
影响因子：
15.9
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Shimizu, Ippei;Minamino, Tohru;Komuro, Issei
尽管许多动物研究表明胰岛素具有心脏保护作用，但临床研究表明胰岛素抵抗（高胰岛素血症）与心力衰竭（HF）之间存在联系。在这里，我们已经证明，过度的心脏胰岛素信号加重啮齿动物的压力超负荷引起的收缩功能障碍。慢性压力超负荷导致肝脏胰岛素抵抗和血浆胰岛素水平升高。与此相反，心脏胰岛素信号上调慢性压力超负荷，因为机械牵张诱导的心肌细胞胰岛素受体的激活和上调胰岛素受体和Irs1的表达。慢性压力超负荷增加了心肌细胞大小和血管分布之间的不匹配，从而诱导心肌缺氧和心肌细胞死亡。抑制高胰岛素血症可显著改善压力超负荷引起的心功能不全，改善心肌缺氧，减少心肌细胞死亡。同样地，心肌细胞特异性胰岛素受体表达的减少防止了心脏缺血和肥大，并减轻了由于压力超负荷引起的收缩功能障碍。相反，用胰岛素治疗1型糖尿病小鼠改善了压力超负荷期间的高血糖症，但增加了心肌缺血和心肌细胞死亡，从而诱导HF。促进血管生成可恢复胰岛素治疗引起的心功能不全。因此，我们认为，使用胰岛素控制高血糖症可能是有害的压力超负荷的设置和胰岛素信号的调制是至关重要的治疗HF。
Although many animal studies indicate insulin has cardioprotective effects, clinical studies suggest a link between insulin resistance (hyperinsulinemia) and heart failure (HF). Here we have demonstrated that excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. Chronic pressure overload induced hepatic insulin resistance and plasma insulin level elevation. In contrast, cardiac insulin signaling was upregulated by chronic pressure overload because of mechanical stretch-induced activation of cardiomyocyte insulin receptors and upregulation of insulin receptor and Irs1 expression. Chronic pressure overload increased the mismatch between cardiomyocyte size and vascularity, thereby inducing myocardial hypoxia and cardiomyocyte death. Inhibition of hyperinsulinemia substantially improved pressure overload-induced cardiac dysfunction, improving myocardial hypoxia and decreasing cardiomyocyte death. Likewise, the cardiomyocyte-specific reduction of insulin receptor expression prevented cardiac ischemia and hypertrophy and attenuated systolic dysfunction due to pressure overload. Conversely, treatment of type 1 diabetic mice with insulin improved hyperglycemia during pressure overload, but increased myocardial ischemia and cardiomyocyte death, thereby inducing HF. Promoting angiogenesis restored the cardiac dysfunction induced by insulin treatment. We therefore suggest that the use of insulin to control hyperglycemia could be harmful in the setting of pressure overload and that modulation of insulin signaling is crucial for the treatment of HF.