近日，首都医科大学教授曲爱娟团队的研究发现Sirtuin 6通过维持血管平滑肌细胞的线粒体稳态减轻胸主动脉瘤的进展。这一研究成果于2025年9月2日发表在国际顶尖学术期刊《中国药理学报》上。

在本研究中，研究人员研究了VSMC SIRT6在AAD中的作用及其分子机制。研究小组发现，在AAD患者的胸主动脉VSMCs中SIRT6的表达水平显著降低。该团队构建了VSMC特异性Sirt6缺陷母主题系，发现即使没有Apoe缺陷背景，VSMC中Sirt6的缺失也会显著加速血管紧张素II （Ang II）诱导的AAD形成和破裂。在人主动脉平滑肌细胞（HASMCs）中，SIRT6的敲低导致线粒体功能障碍和VSMC衰老加速。小组发现SIRT6结合并去乙酰化NRF2， NRF2是线粒体生物发生的关键转录因子。

然而，Sirt6缺乏抑制NRF2并减少编码线粒体复合体蛋白的mRNA。值得注意的是，新开发的小分子SIRT6激动剂MDL-811可有效逆转Ang II诱导的HASMCs线粒体功能障碍。在BAPN诱导的TAAD无主题模型中，每隔一天腹腔注射MDL-811（20mg/kg，连续28天）有效缓解AAD进展，降低死亡率。这些结果表明SIRT6对AAD的发展具有保护作用，用小分子激活剂如MDL-811靶向SIRT6可能是一种很有前景的AAD治疗策略。

据了解，血管平滑层细胞（VSMCs）的进行性丧失是危及生命的疾病主动脉瘤和夹层（AAD）的病理生理基础，但其潜在机制在很大程度上尚不清楚。Sirtuin 6 （SIRT6）是一种III类组蛋白去乙酰化酶，对维持VSMC稳态和预防血管重塑相关疾病至关重要。

附：英文原文

Title: Sirtuin 6 mitigates thoracic aortic aneurysm progression via maintenance of mitochondria homeostasis in vascular smooth muscle cells

Author: Yu, Xiao-ting, Zhao, Nan, Ma, Yu-tao, Jia, Jin-meng, Song, Yan-ting, Liu, Xiao-yan, Xiao, Yao, Jia, Bo, Li, Guang-ming, He, Jin-han, Wang, Sheng, Zhu, Jun-ming, Gonzalez, Frank J., Qu, Ai-juan

Issue&Volume: 2025-09-02

Abstract: Progressive loss of vascular smooth muscle cells (VSMCs) is the pathophysiological basis for aortic aneurysm and dissection (AAD), a life-threatening disease, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for maintenance of VSMC homeostasis and prevention of vascular remodeling-related diseases. In this study, we investigated the role of VSMC SIRT6 in AAD and the molecular mechanism. We showed that the expression levels of SIRT6 were significantly reduced in VSMCs of the thoracic aorta in AAD patients. We constructed a VSMC-specific Sirt6 deficient mouse line and found that loss of Sirt6 in VSMCs dramatically accelerated angiotensin II (Ang II)-induced AAD formation and rupture, even without an Apoe-deficient background. In human aortic smooth muscle cells (HASMCs), knockdown of SIRT6 led to mitochondrial dysfunction and accelerated VSMC senescence. We revealed that SIRT6 bound to and deacetylated NRF2, a key transcription factor for mitochondrial biogenesis. However, Sirt6 deficiency inhibited NRF2 and reduced mRNAs encoding mitochondrial complex proteins. Notably, MDL-811, a newly developed small-molecule SIRT6 agonist, effectively reversed Ang II-induced mitochondrial dysfunction in HASMCs. In a BAPN-induced TAAD mouse model, administration of MDL-811 (20mg/kg, i.p., every other day for 28d) effectively mitigated AAD progression and reduced mortality. These results suggest that SIRT6 plays a protective role against AAD development, and targeting SIRT6 with small-molecule activators such as MDL-811 could represent a promising therapeutic strategy for AAD.

DOI: 10.1038/s41401-025-01628-1

Source: https://www.nature.com/articles/s41401-025-01628-1