Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner.

Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9-39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9-39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.

[1]  Jia Liu,et al.  Correlation between arterial stiffness and coronary flow velocity reserve in subjects with pulse wave velocity >1400 cm/s , 2016, Clinical and experimental hypertension.

[2]  H. Hara,et al.  Glucagon-like peptide-1 protects the murine hippocampus against stressors via Akt and ERK1/2 signaling. , 2015, Biochemical and biophysical research communications.

[3]  R. Chen,et al.  Liraglutide ameliorates renal injury in streptozotocin‑induced diabetic rats by activating endothelial nitric oxide synthase activity via the downregulation of the nuclear factor‑κB pathway. , 2014, Molecular medicine reports.

[4]  A. Basu,et al.  The effect of liraglutide on endothelial function in patients with type 2 diabetes , 2014, Diabetes & vascular disease research.

[5]  N. Ruderman,et al.  Glucagon-Like Peptide-1 (GLP-1) Analog Liraglutide Inhibits Endothelial Cell Inflammation through a Calcium and AMPK Dependent Mechanism , 2014, PloS one.

[6]  J. Oyama,et al.  Do incretins improve endothelial function? , 2014, Cardiovascular Diabetology.

[7]  K. Connelly,et al.  Cardiovascular effects of incretins in diabetes. , 2013, Canadian journal of diabetes.

[8]  D. Giugliano,et al.  Glucagon-Like Peptide 1 Reduces Endothelial Dysfunction, Inflammation, and Oxidative Stress Induced by Both Hyperglycemia and Hypoglycemia in Type 1 Diabetes , 2013, Diabetes Care.

[9]  Jinbo Liu,et al.  Coronary flow velocity reserve is improved by PPAR-α agonist fenofibrate in patients with hypertriglyceridemia. , 2013, Cardiovascular therapeutics.

[10]  Li-yun He,et al.  Low density lipoprotein cholesterol level inversely correlated with coronary flow velocity reserve in patients with Type 2 diabetes , 2013, Journal of geriatric cardiology : JGC.

[11]  Hua Xu,et al.  Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways. , 2013, Journal of molecular endocrinology.

[12]  A. Gnasso,et al.  Exenatide improves endothelial function assessed by flow mediated dilation technique in subjects with type 2 diabetes: Results from an observational research , 2013, Diabetes & vascular disease research.

[13]  J. Koska.  Incretins and preservation of endothelial function. , 2012, Cardiovascular & Hematological Agents in Medicinal Chemistry.

[14]  L. Tao,et al.  Glucagon-Like Peptide 1 Recruits Microvasculature and Increases Glucose Use in Muscle via a Nitric Oxide–Dependent Mechanism , 2012, Diabetes.

[15]  V. Basevi,et al.  Standards of Medical Care in Diabetes—2012 , 2011, Diabetes Care.

[16]  Jinbo Liu,et al.  PPAR-α Agonist Fenofibrate Upregulates Tetrahydrobiopterin Level through Increasing the Expression of Guanosine 5′-Triphosphate Cyclohydrolase-I in Human Umbilical Vein Endothelial Cells , 2011, PPAR research.

[17]  A. Hale,et al.  Rapid, Direct Effects of Statin Treatment on Arterial Redox State and Nitric Oxide Bioavailability in Human Atherosclerosis via Tetrahydrobiopterin-Mediated Endothelial Nitric Oxide Synthase Coupling , 2011, Circulation.

[18]  A. Dear,et al.  A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model , 2011, Diabetes & vascular disease research.

[19]  Jinbo Liu,et al.  Homocysteine impairs coronary artery endothelial function by inhibiting tetrahydrobiopterin in patients with hyperhomocysteinemia. , 2010, American journal of physiology. Endocrinology and metabolism.

[20]  Å. Sjöholm,et al.  Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor , 2010, Molecular and Cellular Endocrinology.

[21]  Zhuoli Zhang,et al.  Peroxisome Proliferator-Activated Receptor-γ (PPARγ) Agonist Improves Coronary Artery Endothelial Function in Diabetic Patients with Coronary Artery Disease , 2010 .

[22]  R. Kawamori,et al.  Inhibition of Monocyte Adhesion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-like Peptide-1 Receptor Agonist, Exendin-4 , 2010, Diabetes.

[23]  G. Wang,et al.  Peroxisome proliferator-activated receptor-gamma(PPARgamma) agonist improves coronary artery endothelial function in diabetic patients with coronary artery disease. , 2010, Journal of International Medical Research.

[24]  B. Viollet,et al.  In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I , 2009, Diabetes.

[25]  A. Dear,et al.  A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules. , 2009, The Journal of endocrinology.

[26]  H. Choi,et al.  Acute Inhibition of Guanosine Triphosphate Cyclohydrolase 1 Uncouples Endothelial Nitric Oxide Synthase and Elevates Blood Pressure , 2008, Hypertension.

[27]  C. Tribouilloy,et al.  Non-invasive assessment of coronary flow and coronary flow reserve by transthoracic Doppler echocardiography: a magic tool for the real world. , 2008, European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology.

[28]  D. Drucker,et al.  Cardioprotective and Vasodilatory Actions of Glucagon-Like Peptide 1 Receptor Are Mediated Through Both Glucagon-Like Peptide 1 Receptor–Dependent and –Independent Pathways , 2008, Circulation.

[29]  R. Rizza,et al.  Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride. , 2007, American journal of physiology. Endocrinology and metabolism.

[30]  Dennis D. Kim,et al.  Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes , 2006, Diabetes, obesity & metabolism.

[31]  Dennis D. Kim,et al.  Long‐term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over‐weight metformin‐treated patients with type 2 diabetes mellitus , 2006, Diabetes, obesity & metabolism.

[32]  K. Channon,et al.  Augmented BH4 by gene transfer restores nitric oxide synthase function in hyperglycemic human endothelial cells. , 2005, Cardiovascular research.

[33]  J. Holst,et al.  Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. , 2004, American journal of physiology. Endocrinology and metabolism.

[34]  J. Boucher,et al.  Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. , 2004, Free radical biology & medicine.

[35]  Aesha Drozdowski,et al.  Standards of medical care in diabetes. , 2004, Diabetes care.

[36]  K. Rockett,et al.  Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. , 2003, The Journal of clinical investigation.

[37]  N. Alp,et al.  GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthase activity, protein levels and dimerisation. , 2002, Cardiovascular research.

[38]  K. Channon,et al.  Mechanisms of Increased Vascular Superoxide Production in Human Diabetes Mellitus: Role of NAD(P)H Oxidase and Endothelial Nitric Oxide Synthase , 2002, Circulation.

[39]  T. Meinertz,et al.  Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus , 2000, Diabetologia.

[40]  R. Ross.  Atherosclerosis is an inflammatory disease , 1999 .

[41]  T Akasaka,et al.  Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the left anterior descending coronary artery by Doppler echocardiography: comparison with invasive technique. , 1998, Journal of the American College of Cardiology.

[42]  P. Zimmet,et al.  Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation , 1998, Diabetic medicine : a journal of the British Diabetic Association.