Advanced glycation end products accelerate ischemia/reperfusion injury through receptor of advanced end product/nitrative thioredoxin inactivation in cardiac microvascular endothelial cells.
The advanced glycation end products (AGEs) are associated with increased cardiac endothelial injury. However, no causative link has been established between increased AGEs and enhanced endothelial injury after ischemia/reperfusion. More importantly, the molecular mechanisms by which AGEs may increase endothelial injury remain unknown. Adult rat cardiac microvascular endothelial cells (CMECs) were isolated and incubated with AGE-modified bovine serum albumin (BSA) or BSA. After AGE-BSA or BSA preculture, CMECs were subjected to simulated ischemia (SI)/reperfusion (R). AGE-BSA increased SI/R injury as evidenced by enhanced lactate dehydrogenase release and caspase-3 activity. Moreover, AGE-BSA significantly increased SI/R-induced oxidative/nitrative stress in CMECs (as measured by increased inducible nitric oxide synthase expression, total nitric oxide production, superoxide generation, and peroxynitrite formation) and increased SI/R-induced nitrative inactivation of thioredoxin-1 (Trx-1), an essential cytoprotective molecule. Supplementation of EUK134 (peroxynitrite decomposition catalyst), human Trx-1, or soluble receptor of advanced end product (sRAGE) (a RAGE decoy) in AGE-BSA precultured cells attenuated SI/R-induced oxidative/nitrative stress, reduced SI/R-induced Trx-1 nitration, preserved Trx-1 activity, and reduced SI/R injury. Our results demonstrated that AGEs may increase SI/R-induced endothelial injury by increasing oxidative/nitrative injury and subsequent nitrative inactivation of Trx-1. Interventions blocking RAGE signaling or restoring Trx activity may be novel therapies to mitigate endothelial ischemia/reperfusion injury in the diabetic population.
Department of Cardiology, Xijing Hospital, The Fourth Military Medical University,15 Changle West Road, Xi’an, China.
Yi
Y
Liu
Yanzhuo
Y
Ma
Rutao
R
Wang
Chenhai
C
Xia
Rongqing
R
Zhang
Kun
K
Lian
Ronghua
R
Luan
Lu
L
Sun
Lu
L
Yang
Wayne B
WB
Lau
Haichang
H
Wang
Ling
L
Tao
D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000473:pathology*; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D009566:Nitrates / Q000737:chemistry / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000633:toxicity*; D013481:Superoxides / Q000378:metabolism; D013879:Thioredoxins / Q000737:chemistry / Q000378:metabolism*
D017127:Glycation End Products, Advanced; D009566:Nitrates; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C495697:Txn1 protein, rat; D013481:Superoxides; D012710:Serum Albumin, Bovine; D009569:Nitric Oxide; D013879:Thioredoxins; D007770:L-Lactate Dehydrogenase