Department of Geratology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Eur J Pharmacol. 2010 Feb 25;628(1-3):140-7. doi: 10.1016/j.ejphar.2009.11.038. Epub 2009 Nov 27.
It is well known that systemic insulin resistance is closely associated with the metabolic syndrome including type 2 diabetes and hypertension. However, it remains unclear whether vascular insulin resistance acts as an early etiologic factor for the development of hypertension. Male spontaneously hypertensive rats (SHRs) aged 5 weeks (young) and 15 weeks (adult) were studied and vascular insulin resistance was assessed as the function of isolated aortic vasodilatory response to insulin in vitro. Compared with Wistar-Kyoto (WKY) rats, adult SHRs exhibited significant hypertension with significantly decreased aortic vasodilatation to insulin, whereas young SHRs had normal blood pressure but exhibited similar vascular insulin resistance. Both young and adult SHRs showed significant downregulated expression of PI3-kinase and decreased insulin-stimulated phosphorylations of Akt and eNOS in vascular tissues. Treatment with rosiglitazone (RSG), an insulin sensitizer, for 2 weeks increased vascular PPARgamma expression and restored PI3-kinase/Akt/eNOS-mediated signaling pathway only in young SHRs. More importantly, this treatment improved aortic vasodilatory response to insulin in young but not in adult SHRs. In summary, vascular insulin resistance, characterized by the impairment of PI3-kinase/Akt/eNOS-mediated signaling in vascular endothelium, may play important roles in endothelial dysfunction and subsequent development of hypertension in normotensive young SHRs.
众所周知，全身胰岛素抵抗与包括 2 型糖尿病和高血压在内的代谢综合征密切相关。然而，血管胰岛素抵抗是否作为高血压发展的早期病因尚不清楚。本研究选用 5 周龄（幼年期）和 15 周龄（成年期）雄性自发性高血压大鼠（SHR）作为研究对象，评估血管胰岛素抵抗的功能为体外分离的主动脉对胰岛素的血管舒张反应。与 Wistar-Kyoto（WKY）大鼠相比，成年 SHR 表现出明显的高血压，其主动脉对胰岛素的血管舒张作用明显降低，而幼年期 SHR 的血压正常，但表现出类似的血管胰岛素抵抗。幼年期和成年 SHR 的血管组织中均显示出 PI3-激酶表达明显下调，胰岛素刺激的 Akt 和 eNOS 磷酸化减少。用胰岛素增敏剂罗格列酮（RSG）治疗 2 周，仅在幼年期 SHR 中增加了血管组织中的 PPARγ 表达，并恢复了 PI3-激酶/Akt/eNOS 介导的信号通路。更重要的是，这种治疗改善了幼年期 SHR 的主动脉对胰岛素的血管舒张反应，但对成年 SHR 没有改善。综上所述，血管胰岛素抵抗表现为血管内皮中 PI3-激酶/Akt/eNOS 介导的信号转导受损，可能在正常血压的幼年期 SHR 内皮功能障碍和随后的高血压发展中发挥重要作用。
