网膜素下调致内皮自噬促发肥胖相关的血管内皮功能障碍

Worldwide, the proportion of adults with a body mass index (BMI) of 25 kg/m2 or greater increased between 1980 and 2013 from 28.8% to 36.9% in men, and from 29.8% to 38.0% in women. Vascular endothelial dysfunction is closely associated with obesity and is considered a key element in the development of atherosclerosis-related cardiovascular deseases in obesity. But the cellular and molecular mecnanisms underlying the pathogenesis of this vascular endothelial dysfunction remain largely elusive. Omentin is an adipocytokine that exists in human blood stream and plays an anti-inflammatory role in vascular tissues. However, nothing is known about the relationship between omentin and vascular endothelial dysfunction. Our latest preliminary experimental results showed that serum omentin levels were decreased, protein expressions of beclin 1, a key member of the lipid-kinase complex involved in initiation and regulation of macroautophagy, the autophagy marker LC3-II and the production of superoxide in mesenteric arteries were significantly increased, and acetyl choline (ACh)-induced vasodilation was reduced in high-fat diet-induced obese rats compared with those in normal control. Treatment of these obese rats with exogenous omentin for 14 days significantly improved the ACh-induced vasodilation. Moreover, the homozygous omentin knockout mice had higher beclin 1, LC3-II and superoxide levels and lower ACh-induced vasodilation in mesenteric arteries. Based on these data, we hypothesized that downregulation of omentin induces autophagy and contributes to vascular endothelial dysfunction in obesity. The present study was designed to determine the exact relationship among omentin, autophagy and endothelial dysfunction in obesity and to investigate the molecular basis. All of these would be tested with both pharmacological and genetic modulations. Clarifying this hypothesis might gain further insight into the pathogenesis of obeses vascular endothelial dysfunction and the diversity of biological activity of omentin.

Lancet最新流行病学数据显示，近年全球超重和肥胖人数急遽增多，已达21亿，占总人数近30%，且其病死率最高的并发症是心血管疾病。血管内皮功能障碍是肥胖相关心脑血管病的始动环节，然而迄今其诱发机制尚未阐明。网膜素是新发现的脂肪因子，可调控能量代谢并减轻血管炎症。申请者新近预实验显示，网膜素敲除小鼠肠系膜微动脉对乙酰胆碱(ACh)的舒血管反应减弱，自噬标记蛋白beclin 1、LC3-Ⅱ增加；肥胖大鼠血清网膜素水平降低，肠系膜微动脉ACh舒血管作用亦降低，beclin 1、LC3-Ⅱ增加，用网膜素治疗14天，可降低上述自噬蛋白，部分恢复舒血管效应。提示，肥胖状态下网膜素水平可能与内皮功能障碍之间存在未知的密切联系。本课题拟在此基础上，验证我们所提出的网膜素下调致内皮自噬增加促发肥胖相关内皮功能障碍的假设并研究其机制，期望为深入认识肥胖状态下内皮功能障碍的发生机理提供实验证据。

全球肥胖或超重人群已经达到了21亿人，几乎相当于30%的全球总人数。血管内皮功能障碍是血管内皮细胞的正常功能发生紊乱的病理过程，是肥胖相关的高血压、冠心病、心力衰竭及脑卒中等重大心脑血管疾病的始动环节，认识内皮功能障碍的发生机制、并探寻有效的干预措施，对早期防治这些疾病具有重要意义。在本项目资助下，申请者在国际上首次发现：① 网膜素-1下调可致肥胖相关内皮功能障碍和高血压，其机制和脂肪细胞PPAR-γ表达减少有关；中药何首乌的有效活性成分二苯乙烯苷（TSG）可通过促进脂肪细胞PPAR-γ与网膜素-1基因启动子结合，增加OMT-1表达，激活血管内皮Akt/eNOS/NO信号，减轻氧化/硝酸应激水平，从而改善内皮功能障碍，延缓肥胖相关高血压的发生。② 过度自噬可促发肥胖大鼠微血管内皮功能障碍，TSG可通过抑制过度自噬部分恢复微血管内皮功能从而发挥降压效应，提示TSG可能成为代谢异常相关高血压的候选治疗药物。③ Akt-mTOR信号通路受损介导的过度自噬可诱发幼年自发性高血压大鼠微血管内皮功能障碍，TSG可通过上调Akt/mTOR通路抑制过度自噬并部分恢复微血管内皮功能。提示自噬可能在高血压前期血管功能障碍和血压变化中发挥作用。④ Tribbles homolog 3（TRIB3）上调可诱导肺动脉胰岛素抵抗（VIR）而促发低氧性肺动脉高压，提示改善血管胰岛素敏感性可能有助于限制缺氧性肺动脉高压的进展。⑤ 胎球蛋白B（FetB）介导的胰岛素受体β（IRβ）酪氨酸磷酸化水平降低及其下游信号激活减少，是糖尿病心肌缺血易损性增加的原因之一。这些发现不仅在理论上揭示了诱发肥胖相关的血管内皮功能障碍和高血压的一个全新机制，为深入认识肥胖性高血压的发病机理及网膜素的生物作用多样性提供了新的实验依据；而且对早期防诊治肥胖性高血压有重要的现实意义，网膜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，建议这些人群或可服用一些中草药及其活性成分（如何首乌或二苯乙烯苷），以期改善血管内皮功能，延缓动脉血压的升高。