GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice.
GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice.
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DOI：
10.2337/db08-1193
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发表时间：
2009-04
期刊：
影响因子：
7.7
通讯作者：
Drucker DJ
中科院分区：
文献类型：
--
作者：
Noyan-Ashraf MH;Momen MA;Ban K;Sadi AM;Zhou YQ;Riazi AM;Baggio LL;Henkelman RM;Husain M;Drucker DJ
胰高血糖素样肽-1受体（GLP-1 R）激动剂用于治疗2型糖尿病，短暂GLP-1给药可改善急性心肌梗死（MI）和经皮血运重建后的人类心脏功能。然而，缺血性心肌损伤前GLP-1 R激活的后果仍不清楚。我们评估了用GLP-1 R激动剂利拉鲁肽预处理的正常和糖尿病小鼠冠状动脉闭塞的病理生理学和结局。雄性C57 BL/6小鼠每天两次接受利拉鲁肽或生理盐水给药，持续7天，随后诱导MI。利拉鲁肽处理小鼠的存活率显著更高。利拉鲁肽降低了心脏破裂（12/60 vs 46/60; P = 0.0001）和梗死面积（21 ± 2% vs 29 ± 3%，P = 0.02），并改善了心输出量（12.4 ± 0.6 vs 9.7 ± 0.6 ml/min; P = 0.002）。利拉鲁肽还调节小鼠心脏中心脏保护基因的表达和活性，包括Akt、GSK 3 β、PPARβ-δ、Nrf-2和HO-1。利拉鲁肽对生存期的影响与体重减轻无关。此外，在实验性MI的糖尿病小鼠中，尽管血糖控制相当，但利拉鲁肽仍具有优于二甲双胍的心脏保护和生存优势。利拉鲁肽的心脏保护作用在停止治疗后4天仍可检测到，并且可能部分是直接的，因为利拉鲁肽在体外以GLP-1 R依赖性方式增加了心肌细胞中环AMP的形成并降低了caspase-3活化的程度。这些发现表明，GLP-1 R激活参与正常和糖尿病小鼠心脏中的促生存途径，导致体内MI后结局改善和生存期延长。
Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat type 2 diabetes, and transient GLP-1 administration improved cardiac function in humans after acute myocardial infarction (MI) and percutaneous revascularization. However, the consequences of GLP-1R activation before ischemic myocardial injury remain unclear. We assessed the pathophysiology and outcome of coronary artery occlusion in normal and diabetic mice pretreated with the GLP-1R agonist liraglutide. Male C57BL/6 mice were treated twice daily for 7 days with liraglutide or saline followed by induction of MI. Survival was significantly higher in liraglutide-treated mice. Liraglutide reduced cardiac rupture (12 of 60 versus 46 of 60; P = 0.0001) and infarct size (21 ± 2% versus 29 ± 3%, P = 0.02) and improved cardiac output (12.4 ± 0.6 versus 9.7 ± 0.6 ml/min; P = 0.002). Liraglutide also modulated the expression and activity of cardioprotective genes in the mouse heart, including Akt, GSK3β, PPARβ-δ, Nrf-2, and HO-1. The effects of liraglutide on survival were independent of weight loss. Moreover, liraglutide conferred cardioprotection and survival advantages over metformin, despite equivalent glycemic control, in diabetic mice with experimental MI. The cardioprotective effects of liraglutide remained detectable 4 days after cessation of therapy and may be partly direct, because liraglutide increased cyclic AMP formation and reduced the extent of caspase-3 activation in cardiomyocytes in a GLP-1R–dependent manner in vitro. These findings demonstrate that GLP-1R activation engages prosurvival pathways in the normal and diabetic mouse heart, leading to improved outcomes and enhanced survival after MI in vivo.
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影响因子：
3
作者：
Kavianipour, M;Ehlers, MR;Gutniak, M
通讯作者：
Gutniak, M
影响因子：
7.7
作者：
Larsen, PJ;Fledelius, C;Tang-Christensen, M
通讯作者：
Tang-Christensen, M
影响因子：
20.1
作者：
Petroff, MGV;Egan, JM;Sollott, SJ
通讯作者：
Sollott, SJ
影响因子：
37.8
作者：
Nikolaidis, LA;Elahi, D;Shannon, RP
通讯作者：
Shannon, RP
影响因子：
15.9
作者：
Burkart, Eileen M.;Sambandam, Nandakurnar;Kelly, Daniel P.
通讯作者：
Kelly, Daniel P.