Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr^-/- mice was partially reversed by pharmacological activation or genetic overexpression of HSL. Selective Gipr inactivation in cardiomyocytes phenocopied Gipr^-/- mice, resulting in improved survival and reduced adverse remodeling following experimental MI. Hence, the cardiomyocyte GIPR regulates fatty acid metabolism and the adaptive response to ischemic cardiac injury. These findings have translational relevance for developing GIPR-based therapeutics.

中文翻译：

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葡萄糖依赖性促胰岛素多肽受体的失活可改善实验性心肌梗塞后的预后。

肠促胰激素激素在胰腺以外发挥多效代谢作用。尽管心脏同时表达两种肠降血糖素受体，但对GIP受体（GIPR）作用的心脏生物学仍未完全了解。在这里，我们显示GIPR激动剂不会损害对心脏缺血的反应。相比之下，吉普尔的基因消除减少了心肌梗塞（MI）引起的心室损伤，并增加了与激素敏感性脂肪酶（HSL）磷酸化水平降低相关的存活率；它还增加了心肌三酰甘油（TAG）的储存量。相反，在离体心脏中直接GIPR激动减少了心肌TAG的储存并增加了脂肪酸的氧化。Gipr中的心脏保护表型^-/-小鼠通过药理学激活或HSL基因过表达而部分逆转。表型复制的Gipr ^-/-小鼠的心肌细胞选择性Gipr失活，导致存活率提高，并降低了实验性MI后的不良重塑。因此，心肌细胞GIPR调节脂肪酸代谢和对缺血性心脏损伤的适应性反应。这些发现对开发基于GIPR的疗法具有翻译意义。