Robichaud Sabrina, Rochon Valérie, Emerton Christina, Laval Thomas, Ouimet Mireille
Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Cardiovascular Metabolism and Cell Biology Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada.
Front Cardiovasc Med. 2024 Feb 16;11:1298014. doi: 10.3389/fcvm.2024.1298014. eCollection 2024.
Atherosclerosis is a chronic inflammatory disease caused by the deposition of lipids within the artery wall. During atherogenesis, efficient autophagy is needed to facilitate efferocytosis and cholesterol efflux, limit inflammation and lipid droplet buildup, and eliminate defective mitochondria and protein aggregates. Central to the regulation of autophagy is the transcription factor EB (TFEB), which coordinates the expression of lysosomal biogenesis and autophagy genes. In recent years, trehalose has been shown to promote TFEB activation and protect against atherogenesis. Here, we sought to investigate the role of autophagy activation during atherosclerosis regression.
Atherosclerosis was established in C57BL/6N mice by injecting AAV-PCSK9 and 16 weeks of Western diet feeding, followed by switching to a chow diet to induce atherosclerosis regression. During the regression period, mice were either injected with trehalose concomitant with trehalose supplementation in their drinking water or injected with saline for 6 weeks. Female mice receiving trehalose had reduced atherosclerosis burden, as evidenced by reduced plaque lipid content, macrophage numbers and IL-1β content in parallel with increased plaque collagen deposition, which was not observed in their male counterparts. In addition, trehalose-treated female mice had lower levels of circulating leukocytes, including inflammatory monocytes and CD4 T cells. Lastly, we found that autophagy flux in male mice was basally higher than in female mice during atherosclerosis progression.
Our data demonstrate a sex-specific effect of trehalose in atherosclerosis regression, whereby trehalose reduced lipid content, inflammation, and increased collagen content in female mice but not in male mice. Furthermore, we discovered inherent differences in the autophagy flux capacities between the sexes: female mice exhibited lower plaque autophagy than males, which rendered the female mice more responsive to atherosclerosis regression. Our work highlights the importance of understanding sex differences in atherosclerosis to personalize the development of future therapies to treat cardiovascular diseases.
动脉粥样硬化是一种由脂质在动脉壁内沉积引起的慢性炎症性疾病。在动脉粥样硬化发生过程中，需要有效的自噬来促进胞葬作用和胆固醇流出，限制炎症和脂滴积累，并清除有缺陷的线粒体和蛋白质聚集体。自噬调节的核心是转录因子EB（TFEB），它协调溶酶体生物发生和自噬基因的表达。近年来，海藻糖已被证明可促进TFEB激活并预防动脉粥样硬化。在此，我们试图研究自噬激活在动脉粥样硬化消退过程中的作用。
通过注射腺相关病毒-前蛋白转化酶枯草溶菌素9（AAV-PCSK9）并给予16周的西式饮食喂养，在C57BL/6N小鼠中建立动脉粥样硬化模型，随后改为普通饮食以诱导动脉粥样硬化消退。在消退期，小鼠分别注射海藻糖并在饮用水中补充海藻糖，或注射生理盐水，持续6周。接受海藻糖治疗的雌性小鼠动脉粥样硬化负担减轻，表现为斑块脂质含量、巨噬细胞数量和白细胞介素-1β含量降低，同时斑块胶原沉积增加，而雄性小鼠未观察到这种情况。此外，经海藻糖治疗的雌性小鼠循环白细胞水平较低，包括炎性单核细胞和CD4 T细胞。最后，我们发现，在动脉粥样硬化进展过程中，雄性小鼠的自噬通量基础水平高于雌性小鼠。
我们的数据表明，海藻糖在动脉粥样硬化消退中存在性别特异性作用，即海藻糖可降低雌性小鼠的脂质含量、炎症反应并增加胶原含量，但对雄性小鼠无效。此外，我们发现两性之间自噬通量能力存在固有差异：雌性小鼠斑块自噬低于雄性，这使得雌性小鼠对动脉粥样硬化消退更敏感。我们的研究强调了了解动脉粥样硬化性别差异对于个性化开发未来心血管疾病治疗方法的重要性。
