Sun Xue-Jiao, Xiao Sheng-Jue, Ma Wen-Qi, Jin Hong, Ren Li-Qun, Yao Yu-Yu, Chen Zheng-Dong, Li Xiao-Xue, Chen Tian, Liu Nai-Feng
Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China.
Am J Physiol Endocrinol Metab. 2025 Jun 1;328(6):E924-E939. doi: 10.1152/ajpendo.00161.2023. Epub 2025 Jan 13.
Autophagic flux blockade and excessive oxidative stress play important roles in the pathogenesis of diabetic vascular calcification (VC). Transcription factor EB (TFEB) is an important regulator of many autophagy-lysosomal related components, which is mainly involved in promoting autophagy process in cells. Nuclear factor erythroid-2 related factor 2 (Nrf2) antioxidant system is considered as one of the key pathways in response to intracellular oxidative stress. Periostin (POSTN), a matrix protein, is widely involved in regulating the formation and maintenance of organs such as bones, teeth, heart valves, and tendons. We have previously reported that POSTN interfered with autophagic flux in an oxidative stress-dependent manner in vascular smooth muscle cells (VSMCs) to aggravate the development of diabetic VC. However, how POSTN interfered with autophagic flux by regulating oxidative stress has not been clarified. This study aims to further explore the roles of TFEB, POSTN, autophagy, and Nrf2 antioxidant system in the development of diabetic VC. Our experimental results revealed that activation of TFEB attenuated diabetic VC by improving autophagic flux and activating Nrf2 antioxidant system, whereas POSTN reduced the autophagic degradation of Kelch-like ECH-associated protein 1 (KEAP1) by inhibiting lysosomal function, thus inhibiting the activation of the Nrf2 antioxidant system, and ultimately abolishing the protective effect of TFEB against diabetic VC. In conclusion, this study uncovers that TFEB play an important role in alleviating diabetic VC by improving autophagic flux and activating Nrf2 antioxidant system, suggesting that TFEB may be a new target for the prevention and treatment of diabetic VC. This study is the first to suggest the protective effect of activation of transcription factor EB (TFEB) against diabetic vascular calcification (VC), emphasizing that activation of TFEB alleviated diabetic VC by improving the autophagic flux and activating the Nuclear factor erythroid-2 related factor 2 (Nrf2) antioxidant system in vascular smooth muscle cells (VSMCs), and revealing that periostin (POSTN) partially abolished the protective effect of TFEB on diabetic VC by inhibiting the autophagic degradation of Kelch-like ECH-associated protein 1 (KEAP1).
自噬流阻断和过度氧化应激在糖尿病血管钙化（VC）的发病机制中起重要作用。转录因子EB（TFEB）是许多自噬 - 溶酶体相关成分的重要调节因子，主要参与促进细胞中的自噬过程。核因子红细胞2相关因子2（Nrf2）抗氧化系统被认为是应对细胞内氧化应激的关键途径之一。骨膜蛋白（POSTN）是一种基质蛋白，广泛参与调节骨骼、牙齿、心脏瓣膜和肌腱等器官的形成和维持。我们之前报道过，POSTN在血管平滑肌细胞（VSMCs）中以氧化应激依赖的方式干扰自噬流，从而加重糖尿病VC的发展。然而，POSTN如何通过调节氧化应激来干扰自噬流尚未阐明。本研究旨在进一步探讨TFEB、POSTN、自噬和Nrf2抗氧化系统在糖尿病VC发展中的作用。我们的实验结果表明，激活TFEB可通过改善自噬流和激活Nrf2抗氧化系统来减轻糖尿病VC，而POSTN通过抑制溶酶体功能减少了 Kelch样ECH相关蛋白1（KEAP1）的自噬降解，从而抑制了Nrf2抗氧化系统的激活，并最终消除了TFEB对糖尿病VC的保护作用。总之，本研究揭示了TFEB通过改善自噬流和激活Nrf2抗氧化系统在减轻糖尿病VC中起重要作用，表明TFEB可能是预防和治疗糖尿病VC的新靶点。本研究首次表明激活转录因子EB（TFEB）对糖尿病血管钙化（VC）具有保护作用，强调激活TFEB通过改善血管平滑肌细胞（VSMCs）中的自噬流和激活核因子红细胞2相关因子2（Nrf2）抗氧化系统来减轻糖尿病VC，并揭示骨膜蛋白（POSTN）通过抑制Kelch样ECH相关蛋白1（KEAP1）的自噬降解部分消除了TFEB对糖尿病VC的保护作用。
