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Exendin-4 Prevents Vascular Smooth Muscle Cell Proliferation and Migration by Angiotensin II via the Inhibition of ERK1/2 and JNK Signaling Pathways.

Nagayama K, Kyotani Y, Zhao J, Ito S, Ozawa K, Bolstad FA, Yoshizumi M - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of U0126 (an ERK1/2 kinase inhibitor) and SP600125 (a JNK inhibitor) on the cell proliferation (A) and migration (B) induced by Ang II in RASMC.The cells were pre-incubated with or without U0126 (30 μM), and SP600125 (3 μM) for 1h prior to exposing to Ang II (100 nM) for 24 h. U0126, and SP600125 are abbreviated as U, and SP. Cell proliferation was evaluated by WST-8 assay and cell migration was evaluated by wound healing assay, respectively. Colorimetric analysis and migrated cell counting analysis of each value was normalized by arbitrarily setting the value of the control cells (ctrl.) to 1. Each value represents the mean ± standard error (S.E.) (n = 6). The asterisks represent significant differences compared with the positive control value (*P < 0.05).
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pone.0137960.g005: Effects of U0126 (an ERK1/2 kinase inhibitor) and SP600125 (a JNK inhibitor) on the cell proliferation (A) and migration (B) induced by Ang II in RASMC.The cells were pre-incubated with or without U0126 (30 μM), and SP600125 (3 μM) for 1h prior to exposing to Ang II (100 nM) for 24 h. U0126, and SP600125 are abbreviated as U, and SP. Cell proliferation was evaluated by WST-8 assay and cell migration was evaluated by wound healing assay, respectively. Colorimetric analysis and migrated cell counting analysis of each value was normalized by arbitrarily setting the value of the control cells (ctrl.) to 1. Each value represents the mean ± standard error (S.E.) (n = 6). The asterisks represent significant differences compared with the positive control value (*P < 0.05).

Mentions: To confirm the possible involvement of ERK1/2 and JNK on Ang II-induced RASMC proliferation and migration, we examined the effects of U0126 (an ERK1/2 kinase inhibitor) and SP600125 (a JNK inhibitor) on Ang II-induced RASMC proliferation and migration. As shown in Fig 5A, both U0126 and SP600125 significantly inhibited Ang II-induced RASMC proliferation. U0126 and SP600125 also showed almost complete inhibition of Ang II-induced RASMC migration (Fig 5B). These findings suggest that ERK1/2 and JNK play important roles in Ang II-induced VSMC proliferation and migration.


Exendin-4 Prevents Vascular Smooth Muscle Cell Proliferation and Migration by Angiotensin II via the Inhibition of ERK1/2 and JNK Signaling Pathways.

Nagayama K, Kyotani Y, Zhao J, Ito S, Ozawa K, Bolstad FA, Yoshizumi M - PLoS ONE (2015)

Effects of U0126 (an ERK1/2 kinase inhibitor) and SP600125 (a JNK inhibitor) on the cell proliferation (A) and migration (B) induced by Ang II in RASMC.The cells were pre-incubated with or without U0126 (30 μM), and SP600125 (3 μM) for 1h prior to exposing to Ang II (100 nM) for 24 h. U0126, and SP600125 are abbreviated as U, and SP. Cell proliferation was evaluated by WST-8 assay and cell migration was evaluated by wound healing assay, respectively. Colorimetric analysis and migrated cell counting analysis of each value was normalized by arbitrarily setting the value of the control cells (ctrl.) to 1. Each value represents the mean ± standard error (S.E.) (n = 6). The asterisks represent significant differences compared with the positive control value (*P < 0.05).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4574935&req=5

pone.0137960.g005: Effects of U0126 (an ERK1/2 kinase inhibitor) and SP600125 (a JNK inhibitor) on the cell proliferation (A) and migration (B) induced by Ang II in RASMC.The cells were pre-incubated with or without U0126 (30 μM), and SP600125 (3 μM) for 1h prior to exposing to Ang II (100 nM) for 24 h. U0126, and SP600125 are abbreviated as U, and SP. Cell proliferation was evaluated by WST-8 assay and cell migration was evaluated by wound healing assay, respectively. Colorimetric analysis and migrated cell counting analysis of each value was normalized by arbitrarily setting the value of the control cells (ctrl.) to 1. Each value represents the mean ± standard error (S.E.) (n = 6). The asterisks represent significant differences compared with the positive control value (*P < 0.05).
Mentions: To confirm the possible involvement of ERK1/2 and JNK on Ang II-induced RASMC proliferation and migration, we examined the effects of U0126 (an ERK1/2 kinase inhibitor) and SP600125 (a JNK inhibitor) on Ang II-induced RASMC proliferation and migration. As shown in Fig 5A, both U0126 and SP600125 significantly inhibited Ang II-induced RASMC proliferation. U0126 and SP600125 also showed almost complete inhibition of Ang II-induced RASMC migration (Fig 5B). These findings suggest that ERK1/2 and JNK play important roles in Ang II-induced VSMC proliferation and migration.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Nara Medical University School of Medicine, Kashihara, Nara, Japan.

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.

No MeSH data available.


Related in: MedlinePlus