Association of serum HMGB2 level with MACE at 1 mo of myocardial infarction: Aggravation of myocardial ischemic injury in rats by HMGB2 via ROS

• Published in: American journal of physiology. Heart and circulatory physiology 2017-03, Vol.312 (3), p.H422-H436
• Main Authors: Liu, Zhu Hui, Dai, Dao Peng, Ding, Feng Hua, Pan, Wen Qi, Fang, Yue Hua, Zhang, Qi, Li, Man, Yang, Ping, Wang, Xiao Qun, Shen, Ying, Wang, Ling Jie, Yan, Xiao Xiang, He, Yu Hu, Yang, Ke, Zhang, Rui Yan, Shen, Wei Feng, Chen, Ying, Lu, Lin
• Format: Article
• Language: English
• Subjects: Acetophenones - pharmacology; Aged; Animals; Apoptosis; Cell Line; Female; Glycation End Products, Advanced - metabolism; Heart - physiopathology; Heart attacks; HMGB2 Protein - blood; HMGB2 Protein - genetics; HMGB2 Protein - toxicity; Humans; Inflammation - pathology; Inflammatory diseases; Ischemia; Male; Middle Aged; Myocardial Ischemia - blood; Myocardium - pathology; NADPH Oxidases - antagonists & inhibitors; Phagosomes; Physiology; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; ST Elevation Myocardial Infarction - blood; ST Elevation Myocardial Infarction - genetics; ST Elevation Myocardial Infarction - pathology; Stroke Volume
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00249.2016

High-mobility group box (HMGB) family is related to inflammatory diseases. We investigated whether serum HMGB2 levels are related to myocardial infarction (MI) severity and major adverse cardiac events (MACE) during MI. We included 432 consecutive patients with ST-segment elevation myocardial infarction and 312 controls. Serum HMGB2 levels were significantly higher in MI patients than in controls. Increased HMGB2 levels were associated with MACE and negatively with ejection fraction in MI patients. HMGB2 was an independent determinant of MACE in logistic regression analysis. HMGB2 protein (10 μg) or saline was injected intramyocardially in MI rats, with or without coadministration of the NADPH oxidase inhibitor apocynin. After 72 h, pathological, echocardiographic, and hemodynamic examinations showed that HMGB2 increased infarct size and worsened cardiac function in MI rats. Moreover, HMGB2 administration enhanced reactive oxygen species (ROS) production, cell apoptosis, inflammation, and autophagosome clearance impairment, which were attenuated by coadministration of apocynin or knock down of receptor for advanced glycation end products (RAGE). In conclusion, increased serum HMGB2 levels are associated with MI severity and MACE at 1 mo. HMGB2 promotes myocardial ischemic injury in rats and hypoxic H9C2 cell damage via ROS provoked by RAGE. We demonstrate that serum high-mobility group box 2 is associated with major adverse cardiac events at 1 mo in myocardial infarction patients. Mechanistically, high-mobility group box 2 promotes reactive oxygen species production via receptor for advanced glycation end products signaling in ischemic myocardium, thereby aggravating cell apoptosis, inflammation, and autophagosome clearance impairment. This study reveals that high-mobility group box 2 is a novel factor enhancing ischemic injury in myocardial infarction.