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Title: Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome

Abstract

Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ET{sub A}R during insulin resistance, ET{sub A}R expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ET{sub A}R expression, but not ET{sub B}R, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation wasmore » decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ET{sub A}R pathway suppressed insulin-induced AKT activation, whereas remained insulin-induced ERK activation. ET-1 and insulin synergistically potentiated migration and proliferation mainly through ET{sub A}R/ERK dependent pathway, which is dominant in VSMCs during modest insulin resistance syndrome. Therefore, ET-1 and ET{sub A}R are potential targets responsible for the observed synergism effect in the hypertensive atherosclerotic process through enhancement of ET-1 binding, ET-1 binding, ET{sub A}R expression, and ET-1-induced mitogenic actions in aortic VSMCs. - Highlights: • ET-1/ET{sub A}R signaling and insulin-induced pERK were high in modest insulin resistance. • ET-1 via ET{sub A}R suppressed insulin-induced pAKT but remained intact pERK in VSMCs. • Insulin potentiated ET-1-induced VSMC mitogenic action was ET{sub A}R/ERK dependent.« less

Authors:
 [1];  [2];  [1];  [2];  [3];  [2];  [4];  [3];  [1];  [1];  [2];  [2];  [2]
  1. Institute of Physiology, National Yang-Ming University, Taipei, Taiwan (China)
  2. (China)
  3. Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (China)
  4. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan (China)
Publication Date:
OSTI Identifier:
22462030
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 460; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AORTA; ARTERIOSCLEROSIS; BLOOD PRESSURE; DIET; ENDOTHELIUM; FEEDING; FRUCTOSE; HYPERGLYCEMIA; HYPERTENSION; INFUSION; INSULIN; MUSCLES; PHOSPHORYLATION; RATS; RECEPTORS; SIGNALS; SYNERGISM

Citation Formats

Lin, Yan-Jie, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Juan, Chi-Chang, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, Kwok, Ching-Fai, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, Hsu, Yung-Pei, Shih, Kuang-Chung, Chen, Chin-Chang, Ho, Low-Tone, E-mail: ltho@vghtpe.gov.tw, Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, and Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome. United States: N. p., 2015. Web. doi:10.1016/J.BBRC.2015.03.017.
Lin, Yan-Jie, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Juan, Chi-Chang, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, Kwok, Ching-Fai, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, Hsu, Yung-Pei, Shih, Kuang-Chung, Chen, Chin-Chang, Ho, Low-Tone, E-mail: ltho@vghtpe.gov.tw, Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, & Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome. United States. doi:10.1016/J.BBRC.2015.03.017.
Lin, Yan-Jie, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Juan, Chi-Chang, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, Kwok, Ching-Fai, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, Hsu, Yung-Pei, Shih, Kuang-Chung, Chen, Chin-Chang, Ho, Low-Tone, E-mail: ltho@vghtpe.gov.tw, Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan, and Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. Fri . "Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome". United States. doi:10.1016/J.BBRC.2015.03.017.
@article{osti_22462030,
title = {Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome},
author = {Lin, Yan-Jie and Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan and Juan, Chi-Chang and Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan and Kwok, Ching-Fai and Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan and Hsu, Yung-Pei and Shih, Kuang-Chung and Chen, Chin-Chang and Ho, Low-Tone, E-mail: ltho@vghtpe.gov.tw and Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan and Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan and Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan},
abstractNote = {Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ET{sub A}R during insulin resistance, ET{sub A}R expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ET{sub A}R expression, but not ET{sub B}R, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ET{sub A}R pathway suppressed insulin-induced AKT activation, whereas remained insulin-induced ERK activation. ET-1 and insulin synergistically potentiated migration and proliferation mainly through ET{sub A}R/ERK dependent pathway, which is dominant in VSMCs during modest insulin resistance syndrome. Therefore, ET-1 and ET{sub A}R are potential targets responsible for the observed synergism effect in the hypertensive atherosclerotic process through enhancement of ET-1 binding, ET-1 binding, ET{sub A}R expression, and ET-1-induced mitogenic actions in aortic VSMCs. - Highlights: • ET-1/ET{sub A}R signaling and insulin-induced pERK were high in modest insulin resistance. • ET-1 via ET{sub A}R suppressed insulin-induced pAKT but remained intact pERK in VSMCs. • Insulin potentiated ET-1-induced VSMC mitogenic action was ET{sub A}R/ERK dependent.},
doi = {10.1016/J.BBRC.2015.03.017},
journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 460,
place = {United States},
year = {2015},
month = {5}
}