脂肪因子visfatin加重斑块易损性的机制研究

Acute coronary syndrome (ACS), mostly triggered by the ruptured atherosclerotic plaque, is responsible for the high mortality worldwide, and thus becomes a hot topic in the field of cardiovascular research. In previous studies, it has already been found that visfatin is not only a biomarker of chronic status in atherosclerosis, but also a critical mediator in the progression of AS. However, the potential role of visfatin in the pathogenesis of vulnerable plaque has not been reported yet. The animal model of MMP9-/-ApoE-/- double-knocked mice was established and then the murine visfatin lentivirus was injected through the local invasion to reveal the influence of visfatin on the stability of vulnerable plaque. Focusing on the key regulatory factors such as matrix metalloproteinases (MMPs) and collagen,the influence of visfatin on plaque vulnerability will be elucidated. Meanwhile, the relative signaling pathway involved in this process will be investigated in vitro. Our rearch will provide a new theoretical support on understanding the pathological mechanism of atherosclerotic plaque vulnerability and may be helpful in designing a novel therapeutic target against ACS.

探讨急性冠脉综合征（ACS）病程中易损斑块的发生机制并寻找有效的干预靶点，已成为心血管研究领域中亟待解决的重要课题之一。在本课题组的前期研究中发现急性ST段抬高性心肌梗死患者急性期的冠脉内脂肪因子visfatin水平较外周血清水平显著升高，这提示visfatin于冠脉内的局部高表达与冠脉急性事件的发生密切相关。然而visfatin在AS易损斑块形成过程中所发挥的作用及其机制国内外尚未见报道。本课题组通过构建visfatin高表达慢病毒及visfatin-shRNA慢病毒转染ApoE-/-小鼠，揭示visfatin对斑块易损性的影响，并围绕影响斑块稳定性的关键因子基质金属蛋白酶-9（MMP-9）、胶原等关键因子，寻找visfatin通过上调MMP-9表达加重斑块易损性的直接证据，并在体外实验中对其相关信号转导通路进行深入研究，旨在为ACS的防治提供新的干预靶点和实验依据。

本课题旨在急性冠脉综合征（ACS）病程中动脉粥样硬化（AS）易损斑块的发生机制并寻找有效的干预靶点。本课题组通过在 ApoE-/- 小鼠颈动脉AS斑块区域局部注射 visfatin高表达慢病毒，成功实现visfatin在AS病变局部的高表达，证实了上调 visfatin在AS斑块局部的表达，可以改变的斑块的组成，加重斑块的易损性，其机制与visfatin上调斑块内基质金属蛋白酶（MMPs）如MMP-1、MMP-2、MMP-8、MMP-9以及ADAMTS4直接相关。同时，本研究还对急性心肌梗死组、稳定性心绞痛组及健康对照组三组外周动脉血样本中的 visfatin 行ELISA检测发现：急性心肌梗死组外周血的visfatin水平显著高于稳定性心绞痛组及健康对照组，通过对60例急性心肌梗死患者冠脉内血样与外周动脉血样标本中visfatin表达水平进行 ELISA检测发现，visfatin在心肌梗死急性期于冠脉内表达水平较外周动脉血样显著升高，进一步佐证了visfatin不仅仅可以作为AS斑块易损性的一个监测标志物，同样作为一个参与者在加重斑块易损性的过程中发挥了作用。