DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion
DPP4 deficiency preserves cardiac function via GLP-1 signaling in rats subjected to myocardial ischemia/reperfusion
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DOI：
10.1007/s00210-011-0665-3
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发表时间：
2011-08-01
影响因子：
3.6
通讯作者：
Su, Ming-Jai
中科院分区：
文献类型：
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作者：
Ku, Hui-Chun;Chen, Wen-Pin;Su, Ming-Jai
据报道，二肽基肽酶 4 (DPP4) 酶抑制可增加血浆胰高血糖素样肽 1 (GLP-1) 水平，从而控制餐后血糖浓度。 DPP4抑制剂和GLP-1类似物均已被批准用作降血糖药。据报道，除了促胰岛素作用外，GLP-1 信号传导还可调节心脏功能。 DPP4 抑制被证明可以提高小鼠心肌梗塞后的存活率，但确切的机制仍不清楚。我们的目的是比较野生型和 DPP4 缺陷大鼠之间缺血/再灌注 (I/R) 的心血管反应，并研究其潜在机制。大鼠冠状动脉闭塞 45 分钟，然后再灌注 2 小时。通过分析压力-容量环来表征心脏功能。与野生型大鼠相比，缺血再灌注后，DPP4 缺陷型大鼠具有更好的心脏功能，梗塞面积和心脏损伤标志物（LDH、ANP 和 BNP）更小，而这种情况可以通过 GLP-1 受体拮抗剂 exendin-(9-39) 减弱。 Exendin-(9-39) 可以降低梗死后 DPP4 缺陷大鼠中心肌 AKT 和 GSK-3 beta 磷酸化水平的增加以及 GLUT4 的较高表达。然而，与野生型大鼠相比，exendin-(9-39) 不能完全消除 DPP4 缺陷大鼠中较小的梗塞面积，这暗示了 GLP-1 受体非依赖性途径的参与。总之，这项研究表明，在 DPP4 缺陷大鼠中，心脏对 I/R 损伤的保护作用得到了证实，这种作用是通过 GLP-1 受体依赖性和受体非依赖性机制介导的。
Dipeptidyl peptidase-4 (DPP4) enzyme inhibition has been reported to increase plasma glucagon-like peptide-1 (GLP-1) level for controlling postprandial glucose concentration. Both DPP4 inhibitors and GLP-1 analog have been approved for antihyperglycemic agents. In addition to the insulinotropic effect, GLP-1 signaling was reported to modulate cardiac function. DPP4 inhibition was shown to improve survival rate after myocardial infarction in mice, but the precise mechanism remains unknown. We aimed to compare the cardiovascular responses of ischemia/reperfusion (I/R) between wild-type and DPP4-deficient rats and investigate the underlying mechanism. Rats were subjected to 45 min of coronary artery occlusion, followed by reperfusion for 2 h. Cardiac function was characterized by analyzing pressure-volume loops. As compared to wild-type rats, after I/R, DPP4-deficient rats had better cardiac performance in association with less infarct size and cardiac injury markers (LDH, ANP, and BNP), which could be attenuated by exendin-(9-39), a GLP-1 receptor antagonist. Exendin-(9-39) could diminish the increased phosphorylation levels of myocardial AKT and GSK-3 beta as well as the higher expression of GLUT4 in post-infarcted DPP4-deficient rats. However, exendin-(9-39) could not completely abrogate the less infarct size in DPP4-deficient rats as compared with that in wild-type rats, implicating the involvement of GLP-1 receptor-independent pathway. In summary, this study demonstrated that the benefit of cardiac protective action against I/R injury was demonstrated in DPP4-deficient rats, which is mediated through both GLP-1 receptor-dependent and receptor-independent mechanisms.