| Summary: | 博士 === 國立陽明大學 === 生理學研究所 === 100 === Insulin resistance in vascular system, an imbalance between insulin action on endothelin-1 (ET-1) and nitric oxide (NO) predisposes to induce endothelial dysfunction. Resistin has been proposed as a link between obesity and insulin resistance and impaired insulin-stimulated signaling pathway. The level of plasma resistin was upregulated in obese mice and people with metabolic syndrome. Previous studies showed that hyperresistinemia was found in patients with coexistence of hypertension and Type 2 diabetes mellitus (T2DM). In endothelial cells, insulin-stimulated eNOS activation was impaired by resistin. These studies suggested that resistin may play an important role in the pathogenesis of insulin resistance-associated cardiovascular diseases. However, the biological function and underlying mechanism on cardiovascular system of resistin in blood pressure are not clear. The major effects of ET-1 and NO on vascular tone are through intracellular calcium. In this study, we explored the effects of resistin on blance between ET-1 and NO in blood pressure in vivo, ET-1-induced increase in vascular smooth muscle cell (VSMC) calcium level in vitro and finally demonstrated the regulation of resistin on vasorelaxation and vasocontraction. First, we produced recombinat resistin in order to resistin infusion in rats. In 3T3-L1 adipocytes, insulin-stimulated phosphorylation of Akt was inhibited by our recombinat resistin. Rats were infused with resistin or saline for 3 hr, at the first hour, plasma insulin, glucose and HOMA-IR index were significantly increased in resistin-infused rats. After 3 hr resistin or saline infusion, there was an increase tendency in plasma insulin and glucose in resistin-infused rats. But insulin-stimulated phosphorylation of IRβ and Akt were inhibited by resistin in aorta, skeletal muscle and adipose tissue. So after 1 hr resistin or saline infusion, the rats were challenged with vasodilators bradykinin and sodium nitroprusside (SNP) or vasoconstrictors ET-1 and the changes of systolic blood pressure (SBP) would be recorded. The results showed that resistin accelerated cardiovascular recovery response to SNP and delayed cardiovascular recovery response to ET-1. An imbalance between NO and ET-1 on blood pressure were induced by resistin infusion. Then the effects of resistin on ET-1-induced increase in VSMC intracellular calcium would be investigated by calcium fluorescet indicator fura-2. We found resistin had potential effects on the ET-1–induced increase in calcium level. And resistin-enhanced ET-1–induced increase in calcium level was reversed by the blockers of store-operated Ca2+ entry (SOCE) and extracellular-signal-regulated kinase (ERK). Also SOCE was enhanced by resistin through ERK pathway. The endogenous expression of the store-operated calcium channel proteins Orai and stromal interaction molecular (STIMs) were characterized in the VSMCs. The resistin-enhanced ET-1–induced increase in calcium level and the resistin-dependent activation of SOCE were abolished under the STIM1-siRNA treatment, indicating that STIM1 played an important role in resistin-enhanced ET-1–induced increase in calcium level in VSMCs. ACh and SNP-induced maximum vasorelaxation was no difference between control and resistin group. But ET-1-induced maximum vasocontraction were enhanced by resistin. In conculsion, acute resistin infusion impaired insulin signaling pathway in aorta, skeletal muscle and adipose tissue and caused plasma insulin and glucose upregulation. An imbalance between ET-1-induced increase and NO-induced decrease in SBP with interfering cardiovascular recovery were induced in resistin-infused rats. Resistin was suggested to exert potential effects on the ET-1–induced increase in calcium by enhancing the activity of ERK-dependent SOCE. Resistin may enhaced ET-1-induced vasocontraction via this mechanism. Results of this study indicated that resistin may play a risk factor in pathological development of metabolic disorder-associated hypertension.
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