title: Inhibition of ALDH2 by O-GlcNAcylation contributes to the hyperglycemic exacerbation of myocardial ischemia/reperfusion injury.
abstract: Although hyperglycemia is causally related to adverse outcomes after myocardial ischemia/reperfusion (I/R), the underlying mechanisms are largely unknown. Here, we investigated whether excessive O-linked-N-acetylglucosamine (O-GlcNAc) modification of acetaldehyde dehydrogenase 2 (ALDH2), an important cardioprotective enzyme, was a mechanism for the hyperglycemic exacerbation of myocardial I/R injury. Both acute hyperglycemia (AHG) and diabetes (DM)-induced chronic hyperglycemia increased cardiac dysfunction, infarct size and apoptosis index compared with normal saline (NS)+I/R rats (P<0.05). ALDH2 O-GlcNAc modification was increased whereas its activity was decreased in AHG+I/R and DM+I/R rats. High glucose (HG, 30mmol/L) markedly increased ALDH2 O-GlcNAc modification compared with Con group (5mmol/L) (P<0.05). ALDH2 O-GlcNAc modification was increased by 62.9% in Con+PUGNAc group whereas it was decreased by 44.1% in Con+DON group compared with Con group (P<0.05). Accordingly, ALDH2 activity was decreased by 18.1% in Con+PUGNAc group whereas it was increased by 17.9% in Con+DON group. Moreover, DON decreased levels of 4-hydroxy-2-nonenal (4-HNE), aldehydes, protein carbonyl accumulation and apoptosis index compared with HG+H/R group (P<0.05). Alda-1, a specific activator of ALDH2, significantly decreased ALDH2 O-GlcNAc modification and improved infarct size, apoptosis index and cardiac dysfunction induced by I/R combined with hyperglycemia. These findings demonstrate that ALDH2 O-GlcNAc modification is a key mechanism for the hyperglycemic exacerbation of myocardial I/R injury and Alda-1 has therapeutic potential for inducing cardioprotection.
authors.affiliation: Department of Emergency, Qilu Hospital, Shandong University, Jinan, China.|Chest Pain Center, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Baoshan
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Emergency, Qilu Hospital, Shandong University, Jinan, China.|Chest Pain Center, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Emergency, Qilu Hospital, Shandong University, Jinan, China.|Chest Pain Center, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Emergency, Qilu Hospital, Shandong University, Jinan, China.|Chest Pain Center, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Qiuhuan
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Emergency, Qilu Hospital, Shandong University, Jinan, China.|Chest Pain Center, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Mengyang
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Emergency, Qilu Hospital, Shandong University, Jinan, China.|Chest Pain Center, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Emergency, Qilu Hospital, Shandong University, Jinan, China.|Chest Pain Center, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Yuguo
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D006031:Glycosylation; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D011499:Protein Processing, Post-Translational; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000444:Aldehyde Dehydrogenase; D000117:Acetylglucosamine
keywords: ALDH2; O-GlcNAcylation; hyperglycemia; myocardial ischemia/reperfusion