Stroke-induced hexokinase 2 in circulating monocytes exacerbates vascular inflammation and atheroprogression

作者全名："Sun, Yang; Zhang, Lujun; Cao, Yu; Li, Xingsheng; Liu, Fan; Cheng, Xiaoxiao; Du, Jianlin; Ran, Haitao; Wang, Zhigang; Li, Yongyong; Feng, Yuxing; Liang, Liwen; Su, Wenhua; Melgiri, Narayan D.; Zhang, Hong; Huang, Rongzhong"

作者地址："[Sun, Yang; Liu, Fan; Cheng, Xiaoxiao; Ran, Haitao; Wang, Zhigang] Chongqing Med Univ, Affiliated Hosp 2, Dept Ultrasound, Chongqing Key Lab Ultrasound Mol Imaging, Chongqing, Peoples R China; [Zhang, Lujun] Second Mil Med Univ, Changhai Hosp, Dept Cardiol, Shanghai, Peoples R China; [Cao, Yu] First Peoples Hosp Yunnan Prov, Dept Cardiothorac Surg, Kunming, Peoples R China; [Li, Xingsheng] Chongqing Med Univ, Affiliated Hosp 2, Dept Geriatr Med, Chongqing, Peoples R China; [Du, Jianlin] Chongqing Med Univ, Affiliated Hosp 2, Dept Cardiol, Chongqing, Peoples R China; [Feng, Yuxing] Ninth Peoples Hosp Chongqing, Dept Rehabil & Pain Med, Chongqing, Peoples R China; [Liang, Liwen; Su, Wenhua; Zhang, Hong] First Peoples Hosp Yunnan Prov, Dept Cardiol, Kunming, Peoples R China; [Melgiri, Narayan D.] Impactys Fdn Biomed Res, San Diego, CA USA; [Huang, Rongzhong] Chongqing Med Univ, Affiliated Hosp 2, Precis Med Ctr, Chongqing Municipal Clin Res Ctr Geriatr & Geronto, Chongqing, Peoples R China; [Huang, Rongzhong] Chongqing Med Univ, Affiliated Hosp 2, Precis Med Ctr, Chongqing Municipal Clin Res Ctr Geriatr & Geronto, 76 Linjiang Rd, Chongqing 400016, Peoples R China"

通信作者："Huang, RZ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Precis Med Ctr, Chongqing Municipal Clin Res Ctr Geriatr & Geronto, 76 Linjiang Rd, Chongqing 400016, Peoples R China."

来源：JOURNAL OF THROMBOSIS AND HAEMOSTASIS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001042616100001

JCR分区：Q1

影响因子：5.5

年份：2023

卷号：21

期号：6

开始页：1650

结束页：1665

文献类型：Article

关键词：atherosclerosis hexokinase 2 HMGB1 stroke toll-like Receptors

摘要："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."

基金机构："National Natural Science Foundation of China [81960095, 81871369]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (grant numbers 81960095 and 81871369). The funders had no role in the study design, data collection and analysis, decision to publish,or preparation of the manuscript"