脂联素通过促进血管旁脂肪内解耦联蛋白-1对抗肥胖引起的内皮功能紊乱及动脉粥样硬化的功能及机理研究

Perivascular adipose tissue (PVAT) plays an active role in regulation of vascular tone by secreting a panel of bioactive molecules. Our preliminary studies found that PVAT exerts dual effects onvascular reactivity: in lean mice, PVAT mildly enhancesendothelium-dependent vasolaxation while in obese mice, the endothelium function was significantly compromised in the presence of PVAT. Further studies indicate that the switch of PVAT from its protective to detrimental roles might be controlled by the adiponectin-UCP1 axis within the PVAT. In the current study, we propose that UCP1 functions as an antioxidative molecule via depleting the mitochondria membrane potential (MMP).During the pathogenesis of obesity, the adiponectin-UCP1 axis is blunted in PVAT. This event causes the elevation of MMP and superoxide production in PVAT and eventually leads to endothelial dysfunction and atherosclerosis. Depletion of MMP by small molecule uncoupler might be a promising strategy to combat obesity-related vascular diseases. To test this hypothesis, we plan to carry out a series of in vitro and in vivo studies, by using adiponectin and UCP1 knockout mice model, along with small molecular uncoupler and lenti-virus based overexpression system. The findings from this study will help to elucidate the underlying mechanisms by which PVAT contributes to obesity-induced endothelial impairment and atherosclerosis.

血管周围脂肪(PVAT)以旁分泌方式调节血管功能。我们发现PVAT对血管内皮具双向调节功能:健康情况下PVAT促进内皮舒张,而在肥胖情况下PVAT致内皮功能受损,上述PVAT的功能转变可能源于PVAT内adiponectin-UCP1轴的调节。基于本课题组研究基础,我们假设:肥胖发生过程中,PVAT内UCP1降低,导致线粒体膜电位(MMP)升高及超氧阴离子过度生成,最终引起内皮功能紊乱和动脉粥样硬化。药理学手段消除脂肪组织MMP可防治肥胖相关血管疾病。除了对血管壁直接作用,adiponectin还通过维持PVAT中UCP1表达,间接发挥血管保护的功能。我们拟采用adipnectin及UCP1 敲除小鼠,并结合线粒体解耦联小分子,通过一系列在体和离体实验,阐明生理状态PVAT内adipnectin-UCP1通路轴在保护血管方面的功能及作用机制,和肥胖病理条件下该通路失调诱发血管病的分子基础。

血管周围脂肪(PVAT)以旁分泌方式调节血管功能。我们发现PVAT对血管内皮具双向调节功能:在健康情况下PVAT促进内皮舒张,而在肥胖情况下PVAT导致内皮功能受损。另一方面，我们发现在肥胖动物模型中，PVAT内的棕色脂肪标记蛋白解耦联蛋白1 （Uncoupling protein 1, UCP1）的表达显著降低。因此利用Ucp1基因敲除小鼠，我们发现UCP 1基因缺失导致小鼠发生更严重的内皮功能紊乱、血管炎症及动脉粥样硬化斑块生成。进一步通过组织水平及细胞水平的研究，我们发现PVAT内UCP1缺失导致线粒体膜电位(MMP)升高及线粒体超氧阴离子过度生成,后者激活炎性小体，从而促进血管局部白介素1beta (interleukin 1beta)水平增加，最终引起内皮功能紊乱和动脉粥样硬化。药理学手段消除脂肪组织MMP(小分子解耦联剂)或抑制IL1通路可防治肥胖相关血管疾病。本项目揭示了肥胖条件下PVAT内UCP1通路在对抗血管炎症方面的功能及作用机制，并为相关心血管疾病的治疗提供了新的靶点和思路。