HMGB1-RAGE axis contributes to myocardial ischemia/reperfusion injury via regulation of cardiomyocyte autophagy and apoptosis in diabetic mice

• Published in: Biological chemistry Vol. 405; no. 3; pp. 167 - 176
• Main Authors: He, De-Wei, Liu, De-Zhao, Luo, Xiao-Zhi, Chen, Chuan-Bin, Lu, Chuang-Hong, Na, Na, Huang, Feng
• Format: Journal Article
• Language: English
• Published: Germany De Gruyter 25.03.2024; Walter de Gruyter GmbH
• Subjects: Animals; Antibodies; Apoptosis; Autophagy; BAX protein; Bcl-2 protein; Benzamides; Cardiomyocytes; Caspase-3; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; diabetic; HMGB1; HMGB1 protein; HMGB1 Protein - metabolism; HMGB1 Protein - pharmacology; Humans; Ischemia; Mice; Myocardial infarction; Myocardial ischemia; myocardial ischemia-reperfusion injury; Myocardial Reperfusion Injury - metabolism; Myocytes, Cardiac - metabolism; Parkin protein; Protein Kinases - metabolism; PTEN-induced putative kinase; RAGE; Reperfusion; Ubiquitin-Protein Ligases - metabolism; diabetic; apoptosis; autophagy; HMGB1; RAGE; myocardial ischemia-reperfusion injury
• ISSN: 1431-6730; 1437-4315; 1437-4315
• DOI: 10.1515/hsz-2023-0134

Patients with acute myocardial infarction complicated with diabetes are more likely to develop myocardial ischemia/reperfusion (I/R) injury (MI/RI) during reperfusion therapy. Both HMGB1 and RAGE play important roles in MI/RI. However, the specific mechanisms of HMGB1 associated with RAGE are not fully clarified in diabetic MI/RI. This study aimed to investigate whether the HMGB1-RAGE axis induces diabetic MI/RI via regulating autophagy and apoptosis. A db/db mouse model of MI/RI was established, where anti-HMGB1 antibody and RAGE inhibitor (FPS-ZM1) were respectively injected after 10 min of reperfusion. The results showed that treatment with anti-HMGB1 significantly reduced the infarct size, serum LDH, and CK-MB level. Similar situations also occurred in mice administrated with FPS-ZM1, though the HMGB1 level was unchanged. Then, we found that treatment with anti-HMGB1 or FPS-ZM1 performed the same effects in suppressing the autophagy and apoptosis, as reflected by the results of lower LAMP2 and LC3B levels, increased Bcl-2 level, reduced BAX and caspase-3 levels. Moreover, the Pink1/Parkin levels were also inhibited at the same time. Collectively, this study indicates that the HMGB1-RAGE axis aggravated diabetic MI/RI via apoptosis and Pink1/Parkin mediated autophagy pathways, and inhibition of HMGB1 or RAGE contributes to alleviating those adverse situations.