Section of Cardiology, Baylor College of Medicine, and the Texas Heart Institute, Baylor St Luke Medical Center, Houston, TX, USA.
School of Medicine, University of Texas Medical Branch, Galveston, TX, USA.
Basic Res Cardiol. 2019 Aug 6;114(5):35. doi: 10.1007/s00395-019-0743-0.
We compared the effects of linagliptin (Lina, a DPP4 inhibitor) and GLP-1 receptor activation by exenatide followed by exendin-4 in an infusion pump (EX) on infarct size (IS), post-infarction activation of the inflammasome and remodeling in wild-type (WT) and db/db diabetic mice. Mice underwent 30 min ischemia followed by 24 h reperfusion. IS was assessed by TTC. Additional mice underwent permanent coronary artery occlusion. Echocardiography was performed 2w after infarction. Activation of the inflammasome in the border zone of the infarction was assessed by rt-PCR and ELISA 2w after reperfusion. Further in vitro experiments were done using primary human cardiofibroblasts and cardiomyocytes exposed to simulated ischemia-reoxygenation. Lina and EX limited IS in both the WT and the db/db mice. Lina and EX equally improved ejection fraction in both the WT and the db/db mice. mRNA levels of ASC, NALP3, IL-1β, IL-6, Collagen-1, and Collagen-3 were higher in the db/db mice than in the WT mice. Infarction increased these levels in the WT and db/db mice. Lina more than EX attenuated the increase in ASC, NALP3, IL-1β, IL-6, Collagen-1 and Collagen-3, TNFα and IL-1β, and decreased apoptosis, especially in the db/db mice. In vitro experiments showed that Lina, but not EX, attenuated the increase in TLR4 expression, an effect that was dependent on p38 activation with downstream upregulation of Let-7i and miR-146b levels. Lina and EX had similar effects on IS and post-infarction function, but Lina attenuated the activation of the inflammasome and the upregulation of collagen-1 and collagen-3 more than direct GLP-1 receptor activation. This effect depends on p38 activation with downstream upregulation of miR-146b levels that suppresses TLR4 expression.
我们比较了利拉利汀（Lina，一种 DPP4 抑制剂）和 exenatide 经泵注（EX）激活 GLP-1 受体对野生型（WT）和 db/db 糖尿病小鼠梗死面积（IS）、梗死后炎症小体激活和重塑的影响。小鼠经历 30 分钟缺血，然后再灌注 24 小时。通过 TTC 评估 IS。另外一些小鼠接受永久性冠状动脉闭塞。梗死后 2 周行超声心动图检查。再灌注 2 周后通过 rt-PCR 和 ELISA 评估梗死边缘区炎症小体的激活。进一步在体外实验中使用模拟缺血再灌注的原代人心肌成纤维细胞和心肌细胞进行实验。Lina 和 EX 可限制 WT 和 db/db 小鼠的 IS。Lina 和 EX 可使 WT 和 db/db 小鼠的射血分数同样得到改善。db/db 小鼠的 ASC、NALP3、IL-1β、IL-6、Collagen-1 和 Collagen-3 的 mRNA 水平高于 WT 小鼠。WT 和 db/db 小鼠的梗死增加了这些水平。与 EX 相比，Lina 更能减轻 ASC、NALP3、IL-1β、IL-6、Collagen-1 和 Collagen-3、TNFα 和 IL-1β 的增加，并减少凋亡，尤其是在 db/db 小鼠中。体外实验表明，Lina 而非 EX 能减轻 TLR4 表达的增加，这种作用依赖于 p38 的激活，其下游 Let-7i 和 miR-146b 水平的上调。Lina 和 EX 对 IS 和梗死后功能有相似的作用，但 Lina 能更有效地减轻炎症小体的激活和 Collagen-1 和 Collagen-3 的上调，而不是直接激活 GLP-1 受体。这种作用依赖于 p38 的激活，其下游 Let-7i 和 miR-146b 水平的上调抑制 TLR4 表达。
