SIRT1-LXR信号诱导泡沫细胞移出动脉粥样硬化斑块的机制

Foam cell egression from artherosclerosis plaques is a pivotal factor for both the development of plaques and therapeutic treatment. Current studies have shown that liver X receptor (LXR) signaling is involved in the mediation of foam cell egression. However, the up-regulation of LXR expression in monocytes did not show complete protection from artherosclerosis formation or curing.Our previous studies revealed that the expression of both SIRT1 and LXR is down-regulated in blood monocytes from patients with hyperlipemia and hypercholesteremia, but NF-kB is up-regulated. SIRT1 is a key molecule in the mechanism of CR extending lifespan of a variety of species of animals and delaying the onset of age-associated diseases such as artherosclearosis. Therefore, we presume that SIRT1 is involved in the mechanism of foam cell egression from artherosclerosis plaques through deaceylating its target molecules LXR and NF-kB. In the present proposal we will use human monocytes in vitro to mimic foam cell formation and egression, and investigate the expression and activity of LXR and NF-kB after up-regulation of SIRT1 by infection of an adenoviral vector carrying SIRT1 gene or down-regulating SIRT1 by RNAi. We will also prepare monocyte specific-expression SIRT1 transgenic mice and SIRT1 knock-down mice by RNAi, and investigate the effect on the formation of artherosclerosis plaques and the degradation of artherosclerosis plaques after transplantation. We will verify our hypothesis through this study and explore the mechanism of foam cell egression. Our study will provide new insight into preventional and therapeutic targets to arthersclerosis.

泡沫细胞能否从动脉粥样硬化斑移出是病灶发展和治疗的关键。最新研究发现肝X受体(LXR)信号参与调节泡沫细胞移出，但单核细胞高表达LXR并不能完全预防和治疗动脉粥样硬化。本课题组发现高血脂和胆固醇病人血单核细胞中除LXR外SIRT1表达也下调，而NF-kB表达上调。SIRT1是能量限制(CR)延长动物寿命延缓动脉硬化等年龄相关疾病发生的关键因子，因此我们推测SIRT1可能通过调节其靶分子LXR和NF-kB的活性参与调控泡沫细胞的移出。本研究拟用单核细胞体外模拟泡味细胞形成和移出实验，利用腺病毒载体高表达SIRT1和RNA干扰抑制SIRT1表达，观察其对泡味细胞形成和外移以及对其靶分子LXR和NF-kB的影响；再用单核细胞特异表达SIRT1转基因小鼠，通过上调和下调SIRT1表达及活性观察其对动脉粥样硬化斑形成及消退的影响，验证我们的假设，深入探讨其调控机制，为防治动脉粥样化提供新的干预靶点。

近年研究表明肝X受体(LXR)信号参与调节泡沫细胞移出，但单核细胞高表达LXR并不能有效预防和治疗动脉粥样硬化。而能量限制(CR)能延长动物的寿命，可有效防治动脉粥样硬化，SIRT1是CR延长寿命的关键因子，因此本研究提出的假设是：SIRT1可能在激活其靶分子LXR的同时也调节其另一靶分子NF-kB的活性抑制炎症反应，共同调控泡沫细胞的移出，抑制动脉粥样硬化的生成，促进斑块的消退。本研究通过体外泡味细胞模型实验，证明上调或激活SIRT1可激活LXR信号通路，同时抑制NF-kB信号通路，从而抑制泡沫细胞的形成，也抑制人血管内皮细胞HUVECs的增殖、移行和血管生成。同时新发现激活SIRT1信号也抑制了促进动脉粥样硬化发生发展的mTOR信号，并证明了SIRT1与mTOR信号有相互作用的关系。通过ApoE-/-小鼠和新西兰大白兔动脉粥样硬化模型的研究证实了SIRT1抗动脉粥样硬化的作用，验证了其调控机制包括①通路激活LXR- CCR7-ACBA1信号通路促进泡沫细胞移出动脉粥样硬化斑块，②通过抑制NF-kB的活性抑制促动脉粥样硬化的炎症反应，③通过抑制mTOR信号通路进一步发挥抗动脉粥样硬化的作用。由此产生的新见解是：SIRT1信号通路与mTOR信号通路有相互抑制作用，SIRT1激活剂SRT1720和mTOR抑制剂雷帕霉素有抗动脉粥样硬化的协同作用。本研究不仅验证了我们的假设，也为动脉粥样硬化的机制研究提出了新的见解，并对预防和治疗动脉粥样硬化，选择新的干预靶点以及措施具有重要的参考价值。