Department of Thoracic and Cardiovascular Surgery, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, China.
Department of Cardiology, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, China.
FASEB J. 2024 Jul 15;38(13):e23765. doi: 10.1096/fj.202400161RR.
The importance of autophagy in atherosclerosis has garnered significant attention regarding the potential applications of autophagy inducers. However, the impact of TAT-Beclin1, a peptide inducer of autophagy, on the development of atherosclerotic plaques remains unclear. Single-cell omics analysis indicates a notable reduction in GAPR1 levels within fibroblasts, stromal cells, and macrophages during atherosclerosis. Tat-beclin1 (T-B), an autophagy-inducing peptide derived from Beclin1, could selectively bind to GAPR1, relieving its inhibition on Beclin1 and thereby augmenting autophagosome formation. To investigate its impact on atherosclerosic plaque progression, we established the ApoE mouse model of carotid atherosclerotic plaques. Surprisingly, intravenous administration of Tat-beclin1 dramatically accelerated the development of carotid artery plaques. Immunofluorescence analysis suggested that macrophage aggregation and autophagosome formation within atherosclerotic plaques were significantly increased upon T-B treatment. However, immunofluorescence and transmission electron microscopy (TEM) analysis revealed a reduction in autophagy flux through lysosomes. In vitro, the interaction between T-B and GAPR1 was confirmed in RAW264.7 cells, resulting in the increased accumulation of p62/SQSTM1 and LC3-II in the presence of ox-LDL. Additionally, T-B treatment elevated the protein levels of p62/SQSTM1, LC3-II, and cleaved caspase 1, along with the secretion of IL-1β in response to ox-LDL exposure. In summary, our study underscores that T-B treatment amplifies abnormal autophagy and inflammation, consequently exacerbating atherosclerotic plaque development in ApoE-/- mice.
自噬在动脉粥样硬化中的重要性引起了人们的广泛关注，自噬诱导剂在动脉粥样硬化中的潜在应用也受到了关注。然而，TAT-Beclin1（自噬诱导肽）对动脉粥样硬化斑块发展的影响尚不清楚。单细胞组学分析表明，在动脉粥样硬化过程中，成纤维细胞、基质细胞和巨噬细胞中的 GAPR1 水平显著降低。Tat-beclin1（T-B）是一种源自 Beclin1 的自噬诱导肽，可选择性地与 GAPR1 结合，解除其对 Beclin1 的抑制作用，从而增加自噬体的形成。为了研究其对动脉粥样硬化斑块进展的影响，我们建立了载脂蛋白 E 小鼠颈动脉粥样硬化斑块模型。令人惊讶的是，静脉注射 Tat-beclin1 可显著加速颈动脉斑块的发展。免疫荧光分析表明，T-B 处理后，动脉粥样硬化斑块内的巨噬细胞聚集和自噬体形成明显增加。然而，免疫荧光和透射电子显微镜（TEM）分析显示，通过溶酶体的自噬通量减少。在体外，我们在 RAW264.7 细胞中证实了 T-B 与 GAPR1 的相互作用，导致在 ox-LDL 存在的情况下 p62/SQSTM1 和 LC3-II 的积累增加。此外，T-B 处理可增加 p62/SQSTM1、LC3-II 和裂解的 caspase 1 的蛋白水平，并在 ox-LDL 刺激下增加 IL-1β 的分泌。综上所述，我们的研究强调，T-B 处理放大了异常的自噬和炎症，从而加剧了 ApoE-/- 小鼠动脉粥样硬化斑块的发展。
