Cholesterol-induced HRD1 reduction accelerates vascular smooth muscle cell senescence via stimulation of endoplasmic reticulum stress-induced reactive oxygen species
J Mol Cell Cardiol. 2024 Jan 2:187:51-64. doi: 10.1016/j.yjmcc.2023.12.007.
Linli Wang 1, Min Wang 2, Haiming Niu 3, Yaping Zhi 4, Shasha Li 5, Xuemin He 6, Zhitao Ren 7, Shiyi Wen 8, Lin Wu 9, Siying Wen 10, Rui Zhang 11, Zheyao Wen 12, Jing Yang 13, Ximei Zhang 14, Yanming Chen 15, Xiaoxian Qian 16, Guojun Shi 17
Affiliations
Affiliations
1 Department of Cardiology, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: wangll39@mail.sysu.edu.cn.
2 Department of Cardiology, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: wangm63@mail.sysu.edu.cn.
3 Department of Critical Care Medicine, Zhongshan People's Hospital, Zhongshan, Guangdong, China. Electronic address: niuhm_sysu@163.com.
4 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: zhiyp@mail2.sysu.edu.cn.
5 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: lishsh85@mail.sysu.edu.cn.
6 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: hexm26@mail.sysu.edu.cn.
7 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: renzht3@mail.sysu.edu.cn.
8 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: wenshy7@mail2.sysu.edu.cn.
9 Department of Cardiology, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: wulin23@mail.sysu.edu.cn.
10 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: wensy9@mail2.sysu.edu.cn.
11 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: zhangr337@mail2.sysu.edu.cn.
12 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: wenzhy6@mail2.sysu.edu.cn.
13 Department of Endocrinology and Metabolism, The Eighth affiliated hospital of Sun Yat-sen University, Shenzhen, Guangdong, China. Electronic address: 18502696981@163.com.
14 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: zhangxm226@mail.sysu.edu.cn.
15 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: chyanm@mail.sysu.edu.cn.
16 Department of Cardiology, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: qianxx@mail.sysu.edu.cn.
17 Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Third affiliated hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address: shigj6@mail.sysu.edu.cn.
Senescence of vascular smooth muscle cells (VSMCs) is a key contributor to plaque vulnerability in atherosclerosis (AS), which is affected by endoplasmic reticulum (ER) stress and Reactive Oxygen Species (ROS) production. However, the crosstalk between ER stress and ROS production in the pathogenesis of VSMC senescence remains to be elucidated. ER-associated degradation (ERAD) is a complex process that clears unfolded or misfolded proteins to maintain ER homeostasis. HRD1 is the major E3 Ligase in mammalian ERAD machineries that catalyzes ubiquitin conjugation to the unfolded or misfolded proteins for degradation. Our results showed that HRD1 protein levels were reduced in human AS plaques and aortic roots from apoE-/- mice fed with high-fat diet (HFD), along with the increased ER stress response. Exposure to Cholesterol in VSMCs activated inflammatory signaling and induced senescence, while reduced HRD1 protein expression. CRISPR Cas9-mediated HRD1 knockout (KO) exacerbated cholesterol- and thapsigargin-induced cell senescence. Inhibiting ER stress with 4-PBA (4-Phenylbutyric acid) partially reversed the ROS production and cell senescence induced by HRD1 deficiency in VSMCs, suggesting that ER stress alone could be sufficient to induce ROS production and senescence in VSMCs. Besides, HRD1 deficiency led to mitochondrial dysfunction, and reducing ROS production from impaired mitochondria partly reversed HRD1 deficiency-induced cell senescence. Finally, we showed that the overexpression of HDR1 reversed cholesterol-induced ER stress, ROS production, and cellular senescence in VSMCs. Our findings indicate that HRD1 protects against senescence by maintaining ER homeostasis and mitochondrial functionality. Thus, targeting HRD1 function may help to mitigate VSMC senescence and prevent vascular aging related diseases. TRIAL REGISTRATION: A real-world study based on the discussion of primary and secondary prevention strategies for coronary heart disease, URL:https://www.clinicaltrials.gov, the trial registration number is [2022]-02-121-01.
