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/ETAR during insulin resistance, ETAR 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, ETAR expression, but not ETBR, 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 ETAR pathway suppressed insulin-induced AKT activation, whereas remained insulin-induced ERK activation. ET-1 and insulin synergistically potentiated migration and proliferation mainly through ETAR/ERK dependent pathway, which is dominant in VSMCs during modest insulin resistance syndrome. Therefore, ET-1 and ETAR are potential targets responsible for the observed synergism effect in the hypertensive atherosclerotic process through enhancement of ET-1 binding, ET-1 binding, ETAR expression, and ET-1-induced mitogenic actions in aortic VSMCs.
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chi-Chang
authors.initials: CC
authors.lastname: Juan
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ching-Fai
authors.initials: CF
authors.lastname: Kwok
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yung-Pei
authors.initials: YP
authors.lastname: Hsu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Kuang-Chung
authors.initials: KC
authors.lastname: Shih
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chin-Chang
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Institute of Physiology, National Yang-Ming University, Taipei, Taiwan; 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. Electronic address: ltho@vghtpe.gov.tw.
authors.forename: Low-Tone
authors.initials: LT
authors.lastname: Ho
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000503:physiopathology; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D006973:Hypertension / Q000209:etiology* / Q000503:physiopathology; D007328:Insulin / Q000008:administration & dosage; D007333:Insulin Resistance; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019332:Endothelin-1; D007328:Insulin
keywords: Endoehtlin-1; Endothelin type A receptor (ET(A)R); Hypertension; Insulin; Insulin resistance; Vascular smooth muscle cells (VSMCs)