Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism.
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.
Diabetes and Metabolism Research Unit, Department of Medicine and Section of Endocrinology, Boston University School of Medicine, Boston, Massachusetts, United States of America; Program of Nutrition and Metabolism, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Nadia M
NM
Krasner
Diabetes and Metabolism Research Unit, Department of Medicine and Section of Endocrinology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Yasuo
Y
Ido
Diabetes and Metabolism Research Unit, Department of Medicine and Section of Endocrinology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Neil B
NB
Ruderman
Diabetes and Metabolism Research Unit, Department of Medicine and Section of Endocrinology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Jose M
JM
Cacicedo
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000704:Analysis of Variance; D001562:Benzimidazoles; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007124:Immunoenzyme Techniques; D054795:Incretins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy*; D000069450:Liraglutide; D053644:Naphthalimides; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
D001562:Benzimidazoles; D054795:Incretins; D053644:Naphthalimides; D034741:RNA, Small Interfering; C458525:STO 609; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D002118:Calcium