exenatide and Neointima

Recently, incretin therapy has attracted increasing attention because of its potential use in tissue-protective therapy. Neuron-derived orphan receptor 1 (NOR1) is a nuclear orphan receptor that regulates vascular smooth muscle cell (VSMC) proliferation. In the present study, we investigated the vascular-protective effect of Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, by inhibiting NOR1 expression in VSMCs.. We classified 7-week-old male 129X1/SvJ mice into control group and Ex-4 low- and high-dose-treated groups fed normal or high-fat diets, respectively. Endothelial denudation injuries were induced in the femoral artery at 8 weeks of age, followed by the evaluation of neointima formation at 12 weeks of age. To evaluate VSMC proliferation, bromodeoxyuridine incorporation assay and cell cycle distribution analysis were performed. NOR1 and cell cycle regulators were detected using immunohistochemistry, western blotting, quantitative reverse-transcription polymerase chain reaction, and luciferase assays.. Ex-4 treatment reduced vascular injury-induced neointima formation compared with controls. In terms of VSMCs occupying the neointima area, VSMC numbers and NOR1-expressing proliferative cells were significantly decreased by Ex-4 in a dose-dependent manner in both diabetic and non-diabetic mice. In vitro experiments using primary cultured VSMCs revealed that Ex-4 attenuated NOR1 expression by reducing extracellular signal-regulated kinase-mitogen-activated protein kinase and cAMP-responsive element-binding protein phosphorylations. Furthermore, in the cell cycle distribution analysis, serum-induced G1-S phase entry was significantly attenuated by Ex-4 treatment of VSMCs by inhibiting the induction of S-phase kinase-associated protein 2.. Ex-4 attenuates neointima formation after vascular injury and VSMC proliferation possibly by inhibiting NOR1 expression.

Topics: Animals; Cells, Cultured; DNA-Binding Proteins; Exenatide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Male; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Nerve Tissue Proteins; Receptors, Steroid; Receptors, Thyroid Hormone

Enhancement of glucagon-like peptide-1 (GLP-1) reduces glucose levels and preserves pancreatic β-cell function, but its effect against restenosis is unknown.. We investigated the effect of subcutaneous injection of exenatide or local delivery of a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) into carotid artery, in reducing the occurrence of restenosis following balloon injury. As a control, we inserted β-galactosidase cDNA in the same vector (rAd-βGAL). Otsuka Long-Evans Tokushima rats were assigned to three groups (n = 12 each): (1) normal saline plus rAd-βGAL delivery (NS + rAd-βGAL), (2) exenatide plus rAd-βGAL delivery (Exenatide + rAd-βGAL), and (3) normal saline plus rAd-GLP-1 delivery (NS + rAd-GLP-1). Normal saline or exenatide were administered subcutaneously from 1 week before to 2 weeks after carotid injury. After 3 weeks, the NS + rAd-βGAL group showed the highest intima-media ratio (IMR; 3.73 ± 0.90), the exenatide + rAd-βGAL treatment was the next highest (2.80 ± 0.51), and NS + rAd-GLP-1 treatment showed the lowest IMR (1.58 ± 0.48, P < 0.05 vs. others). The proliferation and migration of vascular smooth muscle cells and monocyte adhesion were decreased significantly after rAd-GLP-1 treatment, showing the same overall patterns as the IMR. In injured vessels, the apoptosis was greater and MMP2 expression was less in the NS + rAd-GLP-1 than in the exenatide or rAd-βGAL groups. In vitro expressions of matrix metalloproteinases-2 and monocyte chemoattractant protein-1 and nuclear factor-kappa-B-p65 translocation were decreased more in the NS + rAd-GLP-1 group than in the other two groups (all P < 0.05).. Direct GLP-1 overexpression showed better protection against restenosis after balloon injury via suppression of vascular smooth muscle cell migration, increased apoptosis, and decreased inflammatory processes than systemic exenatide treatment. This has potential therapeutic implications for treating macrovascular complications in diabetes.

Topics: Adenoviridae; Animals; Apoptosis; Carotid Artery Injuries; Carotid Artery, External; Cell Adhesion; Cell Movement; Cell Proliferation; Cells, Cultured; Coronary Stenosis; Diabetes Mellitus; Disease Models, Animal; Exenatide; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Glucagon-Like Peptide 1; Human Umbilical Vein Endothelial Cells; Hypoglycemic Agents; Incretins; Male; Matrix Metalloproteinase 2; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Peptides; Rats, Inbred OLETF; Transcription Factor RelA; Transfection; Venoms

Exendin-4 is a glucagon-like peptide-1 receptor agonist that has been used as a drug for treatment of type 2 diabetes. To investigate the effect of exendin-4 on the cardiovascular system, we investigated the impact of exendin-4 on neointimal hyperplasia of the femoral artery after vascular injury. We performed wire-mediated endovascular injury in C57BL/6 mice, followed by administration of exendin-4 24 nmol/kg/day via infusion pump. Four weeks after the injury, exendin-4 treatment significantly attenuated neointimal hyperplasia of the injured artery, although it did not affect glucose metabolism and lipid profile in wild-type mice. Immunofluorescence study revealed abundant expression of GLP-1 receptor on α-smooth muscle actin-positive cells in the injured vessel. Cell proliferation assay using rat aortic smooth muscle cells showed that exendin-4 reduced PDGF-BB induced smooth muscle cell proliferation through the cAMP/PKA pathway. Exendin-4 also inhibited TNFα production by peritoneal macrophages in response to inflammatory stimulus. Our findings indicate that a GLP-1 receptor agonist attenuated neointimal formation after vascular injury. GLP-1 receptor agonists or drugs that raise endogenous GLP-1 level might be effective in the treatment of vascular diseases.

Topics: Actins; Animals; Aorta; Cell Proliferation; Exenatide; Femoral Artery; Fluorescent Antibody Technique; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Infusion Pumps; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Peptides; Rats; Receptors, Glucagon; Vascular System Injuries; Venoms

Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation.

Topics: Animals; Body Weight; Cell Proliferation; Cells, Cultured; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Neointima; Peptides; Rats; Receptors, Glucagon; Signal Transduction; Tunica Intima; Vascular System Injuries; Venoms