SIRT3通过抑制血管老化保护衰老相关腹主动脉瘤形成的机制研究

The incidence of abdominal aortic aneurysm (AAA) increases with aging. The specific mechanism of AAA is unknown and effective treatment is still unavailable. SIRT3 is closely assoicated with aging and is the most important deacetylase in mitochondria，but the role of SIRT3 in AAA formation has not been reported so far. In preliminary studies, we found SIRT3 level was significantly decreased in human AAA patients. Compared with ApoE-/- mice, SIRT3-/-ApoE-/- mice developed significant larger AAA,while drug-induced SIRT3 overexpression in old mouse decreaased AAA diameters. We therefore hypothesized that SIRT3 plays a protective role in age-related AAA. It has been proven that SIRT3 can promote the degradation of mitochondria-derived reactive oxygen species(miotROS) by deacetylating manganese superoxide dismutase（MnSOD）and miotROS is an important player in vascular senescence and AAA. In preliminary studies, we also found that SIRT3 was mainly located in macrophages and vascular smooth muscle cells. SirT3-/-ApoE-/- mice was associated with higher level of AcK68-MnSOD, MMP2 and NLRP3 inflammasome.We therefore hypothesized that SIRT3 may inhibit the formation of AAA by inhibiting NLRP3 inflammasome activation and vascular smooth muscle cell senescence induced by aging. To prove this hypothesis, this study will utilize former established Sirt3-/-ApoE-/- double knock-out mice, combined with bone marrow transplantation techniques. We plan to investigate the role of age-associated SIRT3 reduction in abdominal aortic aneurysm. We hope to provide a new target for AAA prevention and treatment.

腹主动脉瘤(AAA)发病率随年龄增长而增加，其发病机制未明。与衰老密切相关的SIRT3是线粒体内最主要的去乙酰化酶，在AAA中的作用尚无报道。我们发现AAA患者SIRT3表达降低；SIRT3敲除小鼠瘤体增大，而药物诱导老年小鼠SIRT3过表达可缩小瘤体，提示SIRT3参与衰老相关AAA形成。SIRT3通过去乙酰化锰超氧化物歧化酶（MnSOD），增加线粒体活性氧簇（mitoROS）降解，而mitoROS与血管老化密切相关。我们发现SIRT3定位于巨噬细胞及血管平滑肌细胞，SIRT3敲除AAA小鼠乙酰化MnSOD、MMP2及NLRP3水平升高，故推测SIRT3可能通过抑制mitoROS导致的NLRP3炎症小体激活及平滑肌细胞衰老，抑制AAA形成。本项目拟利用已构建的Sirt3-/-及老年小鼠，结合骨髓移植等技术，首次揭示SIRT3下调在AAA中作用，旨在阐明AAA发病机制和寻找潜在药物靶点。

腹主动脉瘤(AAA)发病率随年龄增长而增加，其发病机制未明。与衰老密切相关的SIRT3是线粒体内最主要的去乙酰化酶，在AAA中的作用尚无报道。我们发现，与正常腹主动脉组织相比，SIRT3水平在瘤体局部显著降低。与年轻小鼠相比，老年小鼠SIRT3水平显著降低。在弹力蛋白酶和血管紧张素II构建AAA模型中，老年鼠AAA增多，瘤体增大；而通过腹腔注射HKL，可以上调腹主动脉局部SIRT3水平，并显著缩小瘤体。进而使用SIRT3-/-和SIRT3-/-ApoE-/-小鼠，构建AAA模型，发现SIRT3敲除小鼠的AAA瘤体显著增大，伴有MnSOD和MMP2水平升高。利用SIRT3沉默的人主动脉血管平滑肌细胞和培养基干预，验证了我们的假设，即SIRT3可通过MnSOD-mitoROS通路进行作用。进一步通过腹腔注射Mito-TEMPO抑制小鼠腹腔局部ROS，可以显著缩小SIRT3敲除小鼠的瘤体直径，进而在动物模型层面验证了该通路。本项目揭示了衰老相关的SIRT3下调参与AAA形成的病理生理过程，可能作为新的AAA治疗靶点。