机构：[1]Department of Ultrasound, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing, China[2]Department of Cardiology, Changhai Hospital, Second Military Medical University, Shanghai, China[3]Department of Cardiothoracic Surgery,The First People’s Hospital of Yunnan Province,Kunming,China云南省第一人民医院心脏大血管外科外科片胸外科[4]Department of Geriatric Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China[5]Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China[6]Department of Rehabilitation and Pain Medicine, The Ninth People’s Hospital of Chongqing, Chongqing, China[7]Department of Cardiology,The First People’s Hospital of Yunnan Province,Kunming,China云南省第一人民医院心血管内科内科片[8]Impactys Foundation for Biomedical Research, San Diego, California, USA[9]Precision Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Municipality Clinical Research Center for Geriatrics and Gerontology, Chongqing, China
Background: Stroke accelerates inflammatory monocyte recruitment to the endothelium and consequent atheroprogression via high-mobility group box 1-receptor for advanced glycation end products signaling. Notably, Hmgb1 interacts with multiple tolllike receptors (TLRs) and promotes TLR4-mediated proinflammatory myeloid cell activation. Therefore, TLR-associated mechanism(s) within monocytes may play a role in Hmgb1-driven poststroke atheroprogression. Objectives: We aimed to elucidate the TLR-associated mechanism(s) within monocytes that contribute to stroke-induced exacerbation of atherosclerotic disease. Methods: A weighted gene coexpression network analysis on the whole blood transcriptomes of stroke model mice identified hexokinase 2 (HK2) as a key gene associated with TLR signaling in ischemic stroke. We conducted a cross-sectional analysis of monocyte HK2 levels in patients with ischemic stroke patients. We performed in vitro and in vivo studies using high-cholesterol diet-fed myeloid-specific Hk2-null ApoE-/- (ApoE-/-;Hk2 & UDelta;M & phi;) mice and ApoE-/-;Hk2fl/fl controls. Results: We found markedly higher monocyte HK2 levels in patients with ischemic stroke patients during the acute and subacute phases poststroke. Similarly, stroke model mice displayed a profound increase in monocyte Hk2 levels. Using aortas and aortic valve samples collected from high-cholesterol diet-fed ApoE-/-;Hk2 & UDelta;M & phi; mice and ApoE-/-;Hk2fl/fl controls, we found that stroke-induced monocyte Hk2 upregulation enhanced poststroke atheroprogression and inflammatory monocyte recruitment to the endothelium. Stroke-induced monocyte Hk2 upregulation induced inflammatory monocyte activation, systemic inflammation, and atheroprogression via Il-1 & beta;. Mechanistically, we demonstrated that stroke-induced monocyte Hk2 upregulation was dependent upon Hmgb1-driven p38-dependent hypoxia-inducible factor-1 & alpha; stabilization. Conclusion: Stroke-induced monocyte Hk2 upregulation is a key mechanism underlying poststroke vascular inflammation and atheroprogression.
基金：
National Natural Science Foundation of China [81960095, 81871369]
第一作者机构：[1]Department of Ultrasound, the Second Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ultrasound Molecular Imaging, Chongqing, China
通讯作者：
通讯机构：[9]Precision Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Municipality Clinical Research Center for Geriatrics and Gerontology, Chongqing, China[*1]Precision Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Municipality Clinical Research Center for Geriatrics and Gerontology, No.76, Linjiang road, Yuzhong district, Chongqing, 400016, China.
推荐引用方式(GB/T 7714)：
Sun Yang,Zhang Lujun,Cao Yu,et al.Stroke-induced hexokinase 2 in circulating monocytes exacerbates vascular inflammation and atheroprogression[J].JOURNAL OF THROMBOSIS AND HAEMOSTASIS.2023,21(6):1650-1665.doi:10.1016/j.jtha.2023.02.021.
APA：
Sun, Yang,Zhang, Lujun,Cao, Yu,Li, Xingsheng,Liu, Fan...&Huang, Rongzhong.(2023).Stroke-induced hexokinase 2 in circulating monocytes exacerbates vascular inflammation and atheroprogression.JOURNAL OF THROMBOSIS AND HAEMOSTASIS,21,(6)
MLA：
Sun, Yang,et al."Stroke-induced hexokinase 2 in circulating monocytes exacerbates vascular inflammation and atheroprogression".JOURNAL OF THROMBOSIS AND HAEMOSTASIS 21..6(2023):1650-1665
医学