title: Exendin-4 Prevents Vascular Smooth Muscle Cell Proliferation and Migration by Angiotensin II via the Inhibition of ERK1/2 and JNK Signaling Pathways.
abstract: Angiotensin II (Ang II) is a main pathophysiological culprit peptide for hypertension and atherosclerosis by causing vascular smooth muscle cell (VSMC) proliferation and migration. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, is currently used for the treatment of type-2 diabetes, and is believed to have beneficial effects for cardiovascular diseases. However, the vascular protective mechanisms of GLP-1 receptor agonists remain largely unexplained. In the present study, we examined the effect of exendin-4 on Ang II-induced proliferation and migration of cultured rat aortic smooth muscle cells (RASMC). The major findings of the present study are as follows: (1) Ang II caused a phenotypic switch of RASMC from contractile type to synthetic proliferative type cells; (2) Ang II caused concentration-dependent RASMC proliferation, which was significantly inhibited by the pretreatment with exendin-4; (3) Ang II caused concentration-dependent RASMC migration, which was effectively inhibited by the pretreatment with exendin-4; (4) exendin-4 inhibited Ang II-induced phosphorylation of ERK1/2 and JNK in a pre-incubation time-dependent manner; and (5) U0126 (an ERK1/2 kinase inhibitor) and SP600125 (a JNK inhibitor) also inhibited both RASMC proliferation and migration induced by Ang II stimulation. These results suggest that exendin-4 prevented Ang II-induced VSMC proliferation and migration through the inhibition of ERK1/2 and JNK phosphorylation caused by Ang II stimulation. This indicates that GLP-1 receptor agonists should be considered for use in the treatment of cardiovascular diseases in addition to their current use in the treatment of diabetes mellitus.
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Nagayama
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Kyotani
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Satoyasu
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ozawa
authors.affiliation: Department of Clinical English, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Bolstad
authors.affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshizumi
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014688:Venoms / Q000494:pharmacology*
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D014688:Venoms; D000804:Angiotensin II; D000077270:Exenatide