Non-canonical STING-PERK pathway dependent epigenetic regulation of vascular endothelial dysfunction <i>via</i> integrating IRF3 and NF-<i>κ</i>B in inflammatory response.

Xuesong LI; Xiang Chen; Longbin Zheng; Minghong Chen; Yunjia Zhang; Ruigong Zhu; Jiajing Chen; Jiaming GU; Quanwen Yin; Hong Jiang; Xuan WU; Xian JI; Xin Tang; Mengdie Dong; Qingguo LI; Yuanqing Gao; Hongshan Chen

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Non-canonical STING-PERK pathway dependent epigenetic regulation of vascular endothelial dysfunction via integrating IRF3 and NF-κB in inflammatory response.

Author: Xuesong LI ¹ ; Xiang CHEN ¹ ; Longbin ZHENG ¹ ; Minghong CHEN ¹ ; Yunjia ZHANG ¹ ; Ruigong ZHU ¹ ; Jiajing CHEN ² ; Jiaming GU ¹ ; Quanwen YIN ¹ ; Hong JIANG ¹ ; Xuan WU ¹ ; Xian JI ¹ ; Xin TANG ¹ ; Mengdie DONG ¹ ; Qingguo LI ³ ; Yuanqing GAO ¹ ; Hongshan CHEN ¹
Author Information

1. Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
2. Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai 200040, China.
3. Department of Cardiothoracic Surgery, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 211166, China.
Publication Type:Journal Article
Keywords: Atherosclerosis; BRD4; Endothelial dysfunction; Inflammation; Mitochondrial DNA; PERK; ROS; STING
From: Acta Pharmaceutica Sinica B 2023;13(12):4765-4784
CountryChina
Language:English
Abstract: Inflammation-driven endothelial dysfunction is the major initiating factor in atherosclerosis, while the underlying mechanism remains elusive. Here, we report that the non-canonical stimulator of interferon genes (STING)-PKR-like ER kinase (PERK) pathway was significantly activated in both human and mice atherosclerotic arteries. Typically, STING activation leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor-kappa B (NF-κB)/p65, thereby facilitating IFN signals and inflammation. In contrast, our study reveals the activated non-canonical STING-PERK pathway increases scaffold protein bromodomain protein 4 (BRD4) expression, which encourages the formation of super-enhancers on the proximal promoter regions of the proinflammatory cytokines, thereby enabling the transactivation of these cytokines by integrating activated IRF3 and NF-κB via a condensation process. Endothelium-specific STING and BRD4 deficiency significantly decreased the plaque area and inflammation. Mechanistically, this pathway is triggered by leaked mitochondrial DNA (mtDNA) via mitochondrial permeability transition pore (mPTP), formed by voltage-dependent anion channel 1 (VDAC1) oligomer interaction with oxidized mtDNA upon cholesterol oxidation stimulation. Especially, compared to macrophages, endothelial STING activation plays a more pronounced role in atherosclerosis. We propose a non-canonical STING-PERK pathway-dependent epigenetic paradigm in atherosclerosis that integrates IRF3, NF-κB and BRD4 in inflammatory responses, which provides emerging therapeutic modalities for vascular endothelial dysfunction.