| Summary: | 博士 === 國立陽明大學 === 生理學研究所 === 103 === Professor, Low-Tone Ho Student, Yan-Jie Lin
Endothelin-1 Interacts with Angiotensin II and Insulin in the Development of Hypertension and Atherosclerosis in Insulin Resistance Syndrome
Abstract
Endothelin-1 (ET-1) is the most potent vasoconstrictor which induces long-lasting constriction through the endothelin type A receptor (ETAR) in vascular smooth muscle cells (VSMCs). Angiotensin II (Ang II) is also a vasoconstrictor which acts through Ang II type one receptor (AT1R) to stimulate short-term constriction of VSMCs. Insulin is a peptide hormone with cellular metabolism and growth actions. Subjects with metabolic syndrome are characterized by insulin resistance associated with hypertension, abnormal glucose and lipid homeostasis. Elevated plasma levels of ET-1, Ang II, and insulin have been observed in hypertension animal models with insulin resistant syndrome. A synergistic effect of ET-1 and Ang II on blood pressure has been observed in conscious rat model. However, the potential interactions and underlying mechanisms of ET-1 with Ang II or insulin remain unclear.
To investigate whether Ang II leads to enhancement function and expression of ET-1/ETAR, ET-1-induced vasoconstriction, ET-1 binding, and endothelin receptor expression were examined in isolated endothelium-denuded aorta and A-10 VSMCs. Ang II pretreatment enhanced ET-1-induced vasoconstriction and ET-1 binding of aorta. Further, Ang II enhanced ETAR expression, but not ETBR, in aorta. Moreover, Ang II-enhanced ETAR expression was blunted, and ET-1 binding was reduced by Ang II receptor antagonism or inhibitors of PKC or ERK individually. In summary, Ang II enhances ET-1-induced vasoconstriction by upregulating ETAR expression and ET-1/ETAR binding. These findings support a synergistic effect of Ang II and ET-1 on the development of hypertension.
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 interfering insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant state, we established insulin resistant rat model by feeding high fructose-diet (HFD). We hypothesize that hyperendothelinemia and hyperinsulinemia may cooperate to induce the process of hypertension or atherosclerosis by enhancing the migration and hyperplasia of VSMCs.
To characterize insulin signaling pattern during modest insulin resistant syndrome, we established insulin resistant rat model by feeding high fructose-diet (HFD) and monitored insulin signaling once hypertension occurred during modest insulin resistance. To explore the role of ET-1/ETAR during early-state 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 media wall thickening, accompanied with hyperinsulinemia, hyperendothelinemiam, and insulin resistance, but without overweight and hyperglycemia in the HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ETAR expression, but not ETBR, and binding capacity/affinity of ET-1 increased, accompanied with decreasing increment of insulin-induced Akt phosphorylation and increasing increment of insulin-induced ERK phosphorylation. Furthermore, ET-1 binding and ETAR expression were increased in VSMCs by insulin pretreatment. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-stimulated Akt phosphorylation decreased while the increment of insulin-stimulated ERK phosphorylation remained, just as in the same manner as in insulin resistant model. Moreover, antagonist of ETAR reversed the insulin-stimulated signaling in ET-1 pre-treated VSMCs. Inhibitors of ETAR or ERK reversed the VSMCs migration and proliferation during insulin and ET-1 co-treatment. In summary, ET-1 via ETAR leaded to resistance selectively on insulin-induced AKT pathway, whereas ET-1 via ETAR enhanced activation of insulin-induced ERK signaling leading to the migration and hyperplasia in developing of tunica medical thickening. These findings indicate that hyperinsulinemia may amplify ET-1 binding and ET-1-stimulated hyperplasia and migration via activating ETAR and ERK dependent pathway, whereas insulin resistance and insulin-induced AKT signaling may be deteriorated by ET-1 in modest insulin resistance syndrome. Our observations elucidate pathological roles of ET-1 and ETAR involved in the vascular dysfunctions in modest insulin resistance syndrome, which implicating an interaction of ET-1 with insulin which may be potential target for interventions in the management of cardio-metabolic disease.
In conclusion, the evidence of this thesis provides further insight to the correlation of ET-1 with Ang II and insulin in the pathogenesis of hypertension or atherosclerosis. Taken together, our data suggest ET-1/ETAR may be key regulators in macro-myopathy through vicious circle of ET-1 system and hyperinsulinemia to exacerbate the development of insulin resistance, hypertension, or atherosclerosis. Either antagonism of AT1R or ETAR may be potential therapeutic target for the treatment of hypertension, especially in patients with borderline hypertension or accompanied with early-stage insulin resistance. These evidences also suggest the crosslink of metabolic system and cardiovascular system by interaction of ET-1 system with other hormone such as Ang II or insulin in modest insulin resistant syndrome.
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