title: TNF-α antagonism ameliorates myocardial ischemia-reperfusion injury in mice by upregulating adiponectin.
abstract: Tumor necrosis factor-α (TNF-α) antagonism alleviates myocardial ischemia-reperfusion (MI/R) injury. However, the mechanisms by which the downstream mediators of TNF-α change after acute antagonism during MI/R remain unclear. Adiponectin (APN) exerts anti-ischemic effects, but it is downregulated during MI/R. This study was conducted to investigate whether TNF-α is responsible for the decrease of APN, and whether antagonizing TNF-α affects MI/R injury by increasing APN. Male adult wild-type (WT), APN knockout (APN KO) mice, and those with cardiac knockdowns of APN receptors via siRNA injection were subjected to 30 min of MI followed by reperfusion. The TNF-α antagonist etanercept or globular domain of APN (gAD) was injected 10 min before reperfusion. Etanercept ameliorated MI/R injury in WT mice as evidenced by improved cardiac function, and reduced infarct size and cardiomyocyte apoptosis. APN concentrations were augmented in response to etanercept, followed by an increase in AMP-activated protein kinase phosphorylation. Etanercept still increased cardiac function and reduced infarct size and apoptosis in both APN KO and APN receptors knockdown mice. However, its potential was significantly weakened in these mice compared with the WT mice. TNF-α is responsible for the decrease in APN during MI/R. The cardioprotective effects of TNF-α neutralization are partially due to the upregulation of APN. The results provide more insight into the TNF-α-mediated signaling effects during MI/R and support the need for clinical trials to validate the efficacy of acute TNF-α antagonism in the treatment of MI/R injury.
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China;
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China;
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China;
authors.forename: Qiujun
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Dermatology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China;
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China;
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China;
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Physiology, The Fourth Military Medical University, Xi'an, China; and.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Physiology, The Fourth Military Medical University, Xi'an, China; and Department of Physiology, The Fourth Military Medical University, Xi'an, China; and.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China;
authors.forename: Lize
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China;
authors.forename: Haichang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China; lingtao2006@gmail.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Tao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D000068800:Etanercept; D007074:Immunoglobulin G / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D020011:Protective Agents / Q000494:pharmacology*; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D007074:Immunoglobulin G; D020011:Protective Agents; D054419:Receptors, Adiponectin; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; D055372:AMP-Activated Protein Kinases; D000068800:Etanercept
keywords: adiponectin knockout mice; etanercept; globular domain of adiponectin