Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase in the regulation of endothelial function and blood pressure.
Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase in the regulation of endothelial function and blood pressure.
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DOI：
10.1161/circresaha.108.189316
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发表时间：
2009-05-08
影响因子：
20.1
通讯作者：
Abel ED
中科院分区：
文献类型：
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作者：
Symons JD;McMillin SL;Riehle C;Tanner J;Palionyte M;Hillas E;Jones D;Cooksey RC;Birnbaum MJ;McClain DA;Zhang QJ;Gale D;Wilson LJ;Abel ED
在血管系统中通过磷脂酰肌醇3-激酶/Akt至内皮型一氧化氮合酶（eNOS）的受损的胰岛素信号传导已被假定导致肥胖和其他胰岛素抵抗状态中的动脉功能障碍和高血压。为了研究这一点，我们比较了高脂（HF）饮食小鼠与所有血管组织中胰岛素受体基因消融（TTr-IR−/−）小鼠或Akt 1基因消融（Akt 1 −/−）小鼠血管中的胰岛素信号传导，内皮功能和全身血压。HF小鼠出现肥胖、葡萄糖耐量受损和游离脂肪酸升高，这与内皮功能障碍和高血压有关。基础和胰岛素介导的细胞外信号调节激酶1/2和Akt的磷酸化在血管系统中被保存，但基础和胰岛素刺激的eNOS磷酸化被废除在HF与瘦小鼠的血管。相比之下，尽管TTr-IR−/−小鼠缺乏胰岛素介导的eNOS磷酸化，Akt 1 −/−小鼠缺乏胰岛素介导的eNOS通过Akt 1磷酸化，但基础血管eNOS磷酸化、内皮功能和血压正常。在培养的内皮细胞，6小时的孵育与棕榈酸衰减的基础和胰岛素刺激的eNOS磷酸化和NO的生产，尽管正常激活的细胞外信号调节激酶和Akt。此外，棕榈酸盐孵育的离体动脉损害内皮依赖性，但不血管平滑肌功能。总的来说，这些结果表明，较低的动脉eNOS磷酸化，高血压，血管功能障碍，HF喂养后不导致缺陷的上游信号通过Akt，但从游离脂肪酸介导的eNOS磷酸化的损害。
Impaired insulin signaling via phosphatidylinositol 3-kinase/Akt to endothelial nitric oxide synthase (eNOS) in the vasculature has been postulated to lead to arterial dysfunction and hypertension in obesity and other insulin resistant states. To investigate this, we compared insulin signaling in the vasculature, endothelial function, and systemic blood pressure in mice fed a high-fat (HF) diet to mice with genetic ablation of insulin receptors in all vascular tissues (TTr-IR−/−) or mice with genetic ablation of Akt1 (Akt1−/−). HF mice developed obesity, impaired glucose tolerance, and elevated free fatty acids that was associated with endothelial dysfunction and hypertension. Basal and insulin-mediated phosphorylation of extracellular signal-regulated kinase 1/2 and Akt in the vasculature was preserved, but basal and insulin-stimulated eNOS phosphorylation was abolished in vessels from HF versus lean mice. In contrast, basal vascular eNOS phosphorylation, endothelial function, and blood pressure were normal despite absent insulin-mediated eNOS phosphorylation in TTr-IR−/− mice and absent insulin-mediated eNOS phosphorylation via Akt1 in Akt1−/− mice. In cultured endothelial cells, 6 hours of incubation with palmitate attenuated basal and insulin-stimulated eNOS phosphorylation and NO production despite normal activation of extracellular signal-regulated kinase and Akt. Moreover, incubation of isolated arteries with palmitate impaired endothelium-dependent but not vascular smooth muscle function. Collectively, these results indicate that lower arterial eNOS phosphorylation, hypertension, and vascular dysfunction following HF feeding do not result from defective upstream signaling via Akt, but from free fatty acid–mediated impairment of eNOS phosphorylation.