Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism.
Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism.
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胰高血糖素样肽-1（GLP-1）类似物liraglutide通过钙和AMPK依赖机制抑制内皮细胞炎症。
DOI：
10.1371/journal.pone.0097554
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Cacicedo JM
中科院分区：
文献类型：
--
作者：
Krasner NM;Ido Y;Ruderman NB;Cacicedo JM
利拉鲁肽是一种胰高血糖素样肽-1（GLP-1）模拟物，用于治疗2型糖尿病。与内源性GLP-1的作用相似，利拉鲁肽可增强胰岛素的餐后释放，抑制胰高血糖素释放并增加饱腹感。最近的流行病学研究和临床试验表明，GLP-1模拟物治疗也可能降低糖尿病患者发生心血管疾病的风险。这种作用的机制尚未确定;然而，一种可能性是它们可能通过对血管内皮的直接作用来实现。由于内皮的低度炎症是动脉粥样硬化性心血管疾病（ASCVD）发病机制中的早期事件，因此我们确定了利拉鲁肽对培养的人主动脉内皮细胞（HAEC）中炎症的影响。利拉鲁肽降低了对TNFα和LPS刺激的炎症反应，表现为粘附分子VCAM-1和E-选择素的蛋白表达降低以及THP-1单核细胞粘附降低。发现这是由于细胞Ca 2+和几种对Ca 2+敏感的分子增加所致，这些分子在内皮细胞中具有已知的抗炎作用，包括CaMKKβ、CaMKI、AMPK、eNOS和CREB。用STO-609（一种CaMKK抑制剂）处理细胞，可降低AMPK、CaMKI的活化以及利拉鲁肽对TNFα和LPS诱导的单核细胞粘附的抑制。同样，针对AMPK的shRNA的表达抵消了利拉鲁肽的抗炎作用。结果表明，利拉鲁肽对HAEC具有较强的抗炎作用。他们还证明，这是由于其能够增加细胞内Ca 2+并激活CAMKKβ，从而激活AMPK。
Liraglutide is a glucagon-like peptide-1 (GLP-1) mimetic used for the treatment of Type 2 diabetes. Similar to the actions of endogenous GLP-1, liraglutide potentiates the post-prandial release of insulin, inhibits glucagon release and increases satiety. Recent epidemiological studies and clinical trials have suggested that treatment with GLP-1 mimetics may also diminish the risk of cardiovascular disease in diabetic patients. The mechanism responsible for this effect has yet to be determined; however, one possibility is that they might do so by a direct effect on vascular endothelium. Since low grade inflammation of the endothelium is an early event in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), we determined the effects of liraglutide on inflammation in cultured human aortic endothelial cells (HAECs). Liraglutide reduced the inflammatory responses to TNFα and LPS stimulation, as evidenced by both reduced protein expression of the adhesion molecules VCAM-1 and E-Selectin, and THP-1 monocyte adhesion. This was found to result from increased cell Ca2+ and several molecules sensitive to Ca2+ with known anti inflammatory actions in endothelial cells, including CaMKKβ, CaMKI, AMPK, eNOS and CREB. Treatment of the cells with STO-609, a CaMKK inhibitor, diminished both the activation of AMPK, CaMKI and the inhibition of TNFα and LPS-induced monocyte adhesion by liraglutide. Likewise, expression of an shRNA against AMPK nullified the anti-inflammatory effects of liraglutide. The results indicate that liraglutide exerts a strong anti-inflammatory effect on HAECs. They also demonstrate that this is due to its ability to increase intracellular Ca2+ and activate CAMKKβ, which in turn activates AMPK.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
3.7
作者：
Cuthbertson DJ;Irwin A;Gardner CJ;Daousi C;Purewal T;Furlong N;Goenka N;Thomas EL;Adams VL;Pushpakom SP;Pirmohamed M;Kemp GJ
通讯作者：
Kemp GJ
影响因子：
4.8
作者：
Bullock, BP;Heller, RS;Habener, JF
通讯作者：
Habener, JF
影响因子：
2.4
作者：
Gaspari, Tracey;Liu, HongBin;Dear, Anthony E.
通讯作者：
Dear, Anthony E.
影响因子：
4
作者：
CULLINAN, CA;BRADY, EJ;LEIBOWITZ, MD
通讯作者：
LEIBOWITZ, MD