中国药科大学吴照球课题组报道了基因和药物靶向蜗牛通过减轻斑块内内皮功能障碍和相关炎症抑制动脉粥样硬化。这一研究成果发表在2025年3月25日出版的国际学术期刊《中国药理学报》上。

研究团队之前的研究表明，锌指转录因子Snail主要在胚胎血管内皮细胞（ECs）中表达，而ECs中Snail的缺失会导致血管发育的严重缺陷，并导致胚胎致死性降低。蜗牛在出生后基本不存在，在ECs中诱导缺失蜗牛对出生后发育或成年小鼠的生理性血管生成没有影响。在本研究中，研究小组研究了在病理性血管生成过程中，蜗牛是否在血管内皮细胞中被重新激活。动脉粥样硬化斑块的形成或可能在动脉粥样硬化的进展中发挥功能作用。课题组人员发现Snail的表达水平在人和非主题动脉粥样硬化斑块的ECs中显著升高，并与疾病严重程度相关。在动脉粥样硬化加速和典型motheme模型中，他莫昔芬诱导的ECs特异性Snail缺失可显著降低斑块内内皮功能障碍、炎症和脂质摄取，同时增强斑块稳定性。通过对ApoE–/–SnailiΔEC和ApoE–/–Snailfl/fl动脉血管的ECs进行scRNA测序，研究人员发现Snail缺失显著降低了Ccl5和Cxcl10启动子上的组蛋白乙酰化，从而降低了Ccl5 / Cxcl10驱动的血管损伤和炎症。重组CXCL10蛋白（2μg/kg，静脉注射，每周1次，连续3周）可有效恢复ECs特异性蜗牛缺失小鼠的动脉粥样硬化。最后，小组开发了一种口服生物利用的小分子蜗牛抑制剂LFW273，在小鼠中显示出有效的抗动脉粥样硬化作用。这些结果表明蜗牛是一种有希望的治疗动脉粥样硬化疾病的靶点。

研究人员表示，斑块内内皮功能障碍和相关的炎症有助于动脉粥样硬化的进展。

附：英文原文

Title: Genetic and pharmacological targeting of Snail inhibits atherosclerosis by relieving intraplaque endothelium dysfunction and associated inflammation

Author: Ren, Bo-xue, Zeng, Zhao-lan, Deng, Li, Hu, Jia-meng, Chen, Ming-zhen, Jiang, Hao-wei, Zang, Chen-zi, Fang, Shen-tong, Weiss, Stephen J., Liu, Jie, Fu, Rong, Wu, Zhao-qiu

Issue&Volume: 2025-03-25

Abstract: The intraplaque endothelium dysfunction and associated inflammation contribute to the progression of atherosclerosis. We previously show that zinc-finger transcription factor Snail is predominantly expressed in embryonic vascular endothelial cells (ECs), and deletion of Snail in ECs induces severe defects in vascular development and thus causes embryonic lethality. Snail is essentially absent at postnatal stage, and inducible deletion of Snail in ECs has no impact on physiological angiogenesis in postnatally developing or adult mice. In this study we investigated whether Snail was reactivated in vascular ECs during pathologically angiogenic process (e.g. the formation of atherosclerotic plaque) or could play a functional role in atherosclerosis progression. We showed that the expression levels of Snail were significantly elevated in ECs of human and mouse atherosclerotic plaques, and associated with the disease severity. In the accelerated and canonical mouse models of atherosclerosis, tamoxifen-inducible, EC-specific Snail deletion significantly reduced intraplaque endothelial dysfunction, inflammation and lipid uptake accompanied by enhanced plaque stability. By conducting scRNA-sequencing in ECs of ApoE–/–SnailiΔEC versus ApoE–/–Snailfl/fl arterial vessels, we demonstrated that Snail deletion significantly decreased histone acetylation on Ccl5 and Cxcl10 promoters, thereby decreased CCL5/CXCL10-driven vascular damage and inflammation. Administration with recombinant CXCL10 protein (2 μg/kg, i.v., once per week for three weeks) efficiently restored atherosclerosis in EC-specific Snail-deleted mice. Finally, we developed an orally bioavailable small-molecule Snail inhibitor LFW273 that displayed potent anti-atherosclerotic effects in mice. These results reveal Snail as a promising therapeutic target in atherosclerotic disease.

DOI: 10.1038/s41401-025-01519-5

Source: https://www.nature.com/articles/s41401-025-01519-5