自发性高血压大鼠血管胰岛素抵抗的新机制：低脂联素血症及其诱导的APPL1表达降低

Hypertension is by far the most common cardiovascular disease worldwide. We previously demonstated that vascular insulin resistance (VIR), characterized by the impairment of PI3K/Akt/eNOS-mediated signaling in vascular endothelium, may play important roles in endothelial dysfunction and subsequent development of hypertension in normotensive young (5-week-old) spontaneously hypertensive rats (SHRs) (Eur J Pharmacol, 2010). However, the mechanisms contributing to VIR in SHRs remains largely elusive. On the one hand, we demonstrated that adiponectin protects the endothelium against hyperlipidemic injury by attenuating oxidative/nitrative stress (Am J Physiol Endocrinol Metab, 2007). Adiponectin therapy lowered the elevated blood pressure of salt-fed adiponectin KO mice to those of the wild type. On the other hand, a case-control study showed that a lower plasma adiponectin concentration is significantly associated with hypertension, and hypoadiponectinemia is one of the independent risk factors for hypertension. These results suggest that the plasma adiponectin concentration is closely related to the endothelial dysfunction and blood pressure changes. Our further experiments showed that plasma adiponectin levels and APPL1 (the first identified protein that interacts directly with adiponectin receptors and mediates adiponectin signaling and its insulin sensitization in metabolism) expression in mesenteric arteries of young SHRs were significantly lower than those of WKY control rats. Based on these data, we hypothesized that hypoadiponectinemia and its induced APPL1 downregulation contributes to the development of VIR in SHRs. The present study was designed to determine the exact relationship among vasoactive actions of insulin, hypoadiponectinemia and APPL1 expression in SHRs and also determine whether adiponectin modulates insulin signaling pathways in an APPL1-dependent fasion in endothelial cells and if so, to inveatigate its molecular basis. All of these would be tested both in adiponectin and APPL1 KO mice. Clarifying this hypothesis might gain further insight into the pathogenesis of hypertension and provide novel possible targets for antihypertensive treatment.

高血压是发病率最高的心血管疾病，严重危害人类健康。我们已证实，在幼年自发性高血压大鼠（SHR），胰岛素的舒血管效应减弱（血管胰岛素抵抗，VIR），且先于血压升高而发生（EJP,2010），但诱发VIR的机制尚不清楚。临床研究显示低脂联素血症是高血压的独立危险因素；我们证实脂联素可保护高脂血症大鼠内皮功能（AJP,2007）。提示脂联素水平与血管功能及动脉血压密切相关。我们新近的预实验表明，幼年SHR血浆脂联素水平及其受体后信号分子APPL1的血管表达降低，而脂联素治疗可部分恢复APPL1表达及胰岛素的舒血管效应，且脂联素敲除小鼠亦存在VIR，提示脂联素-APPL1信号受损可能是诱发高血压VIR的机制之一。本项目拟在前期基础上，应用药理学与基因干预方法，研究高血压状态下脂联素水平与APPL1血管表达对血管胰岛素敏感性的影响及机制，期望为深入认识高血压的发病机理并探索早期防治策略提供实验依据。

目前我国高血压患者约占全球高血压总人数的1/5，至少有2.7亿人，且高血压导致死亡的人数每年高达150万，是国人健康的“无形杀手”。彻底阐明高血压的早期发病机制，寻找针对动脉血压升高的有效防治策略和靶点，对实现高血压及其并发症的早防、早诊、早治有极其重要的意义。在本项目资助下，申请者在国际上首次发现：① 高血压前期的幼年自发性高血压大鼠（ySHR）存在血管胰岛素抵抗，其机制与低脂联素血症及其诱发的APPL1表达降低有关；② 早期有氧运动的干预可改善SHR血管胰岛素抵抗，从而限制和延缓高血压发展，其机制与运动抑制血管GRK2表达和活性从而改善胰岛素激活的Akt-eNOS信号通路有关；③ 在高血压前期给予厚朴酚干预可改善血管胰岛素抵抗、延缓血压升高，该作用依赖于上调SHRs血管组织PPARγ表达、减少TRB3表达进而增强Akt/eNOS活性，提示厚朴酚可能作为一种早期抗高血压药物在高血压前期使用；④ 高盐饮食可加重糖尿病造成的血管损伤及功能障碍，其机制与诱导窖蛋白-1（Cav-1）上调并抑制eNOS生成NO、以及促进氧化应激有关，提示适度抑制Cav-1的表达可能是延缓糖尿病状态下盐敏性高血压发病的有效策略之一；⑤ 长期摄食-亚麻酸（ALA）可通过抗炎和抗氧化应激/硝化应激作用改善糖尿病状态下的血管内皮功能障碍，从而延缓糖尿病血管病变的发生和发展。这些实验结果不仅在理论上揭示了诱发血管胰岛素抵抗的一个全新机制，为深入认识高血压的发病机理及脂联素的生物作用多样性提供了新的实验依据；而且对早期防诊治高血压有现实意义，脂联素可能成为早期筛选高血压易患个体的血清标志物，而一旦被确认为高血压易患个体或处于高血压前期（正常高值血压），这些人群应开始长期有氧运动锻炼、减少膳食中盐分的摄入量、或服用有效的中草药活性成分（如厚朴酚或亚麻酸等），以期改善血管内皮功能，延缓动脉血压的升高。