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.
Highlights
The pathogenesis of atherosclerosis is multifactorial, including vasoconstriction, thromboembolism, and vascular smooth muscle cell (VSMC) proliferation and migration [1]
We examined the effect of exendin-4 on 100 nM of angiotensin II (Ang II)-induced rat aortic smooth muscle cells (RASMC) proliferation
Exendin-4 exhibited a concentration-dependent inhibition on Ang II-induced RASMC proliferation and a significant difference in the proliferation of RASMC was observed at 10 nM (Fig 2B)
Summary
The pathogenesis of atherosclerosis is multifactorial, including vasoconstriction, thromboembolism, and vascular smooth muscle cell (VSMC) proliferation and migration [1]. Exendin-4 Prevents VSMC Proliferation and Migration by Angiotensin II hypertension and atherosclerosis [2]. Ang II has various actions on VSMC; modulating vasomotor tone, regulating cell growth and apoptosis, influencing cell migration and extracellular matrix deposition, causing inflammatory reactions, and stimulating production of other growth factors and vasoconstrictors [3]. Earlier studies have suggested that the Ang II-induced cellular responses are attributable, in part, to the phosphorylation of intracellular signaling molecules including the mitogen-activated protein (MAP) kinase family, which includes extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK) [4]. Ang II has been reported as phosphorylating ERK1/2 and JNK in VSMC, members of the MAP kinase family [5] [6]
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