eIF2α-mediated integrated stress response links multiple intracellular signaling pathways to reprogram vascular smooth muscle cell fate in carotid artery plaque
Jichang Luo,
Xiao Zhang,
Wenjing Li,
Tao Wang,
Shengyan Cui,
Tianhua Li,
Yilin Wang,
Wenlong Xu,
Yan Ma,
Bin Yang,
Yumin Luo,
Ge Yang,
Ran Xu,
Liqun Jiao
Affiliations
Jichang Luo
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China; China International Neuroscience Institute (China-INI), Beijing, China
Xiao Zhang
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China; China International Neuroscience Institute (China-INI), Beijing, China
Wenjing Li
Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China; School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China
Tao Wang
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China; China International Neuroscience Institute (China-INI), Beijing, China
Shengyan Cui
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China; China International Neuroscience Institute (China-INI), Beijing, China
Tianhua Li
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China; China International Neuroscience Institute (China-INI), Beijing, China
Yilin Wang
Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China
Wenlong Xu
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China; China International Neuroscience Institute (China-INI), Beijing, China
Yan Ma
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China; China International Neuroscience Institute (China-INI), Beijing, China
Bin Yang
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China; China International Neuroscience Institute (China-INI), Beijing, China
Yumin Luo
Institute of Cerebrovascular Disease Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China
Ge Yang
Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China; School of Artificial Intelligence, University of Chinese Academy of Sciences, Beijing, China; Corresponding author. Laboratory of Computational Biology and Machine Intelligence, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
Ran Xu
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China; China International Neuroscience Institute (China-INI), Beijing, China; Corresponding author. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
Liqun Jiao
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China; China International Neuroscience Institute (China-INI), Beijing, China; Department of Interventional Radiology, Xuanwu Hospital, Capital Medical University, Beijing, China; Corresponding author. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
Background: Carotid arterial atherosclerotic stenosis is a well-recognized pathological basis of ischemic stroke; however, its underlying molecular mechanisms remain unknown. Vascular smooth muscle cells (VSMCs) play fundamental roles in the initiation and progression of atherosclerosis. Organelle dynamics have been reported to affect atherosclerosis development. However, the association between organelle dynamics and various cellular stresses in atherosclerotic progression remain ambiguous. Methods: In this study, we conducted transcriptomics and bioinformatics analyses of stable and vulnerable carotid plaques. Primary VSMCs were isolated from carotid plaques and subjected to histopathological staining to determine their expression profiles. Endoplasmic reticulum (ER), mitochondria, and lysosome dynamics were observed in primary VSMCs and VSMC cell lines using live-cell imaging. Moreover, the mechanisms underlying disordered organelle dynamics were investigated using comprehensive biological approaches. Results: ER whorls, a representative structural change under ER stress, are prominent dynamic reconstructions of VSMCs between vulnerable and stable plaques, followed by fragmented mitochondria and enlarged lysosomes, suggesting mitochondrial stress and lysosomal defects, respectively. Induction of mitochondrial stress alleviated ER stress and autophagy in an eukaryotic translation initiation factor (eIF)-2α-dependent manner. Furthermore, the effects of eIF2α on ER stress, mitochondrial stress, and lysosomal defects were validated using clinical samples. Conclusion: Our results indicate that morphological and functional changes in VSMC organelles, especially in ER whorls, can be used as reliable biomarkers for atherosclerotic progression. Moreover, eIF2α plays an important role in integrating multiple stress-signaling pathways to determine the behavior and fate of VSMCs.
