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.
Subject(s)
Adiponectin/metabolism , Immunoglobulin G/pharmacology , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/prevention & control , Myocardium/metabolism , Protective Agents/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , AMP-Activated Protein Kinases/metabolism , Adiponectin/deficiency , Adiponectin/genetics , Animals , Apoptosis/drug effects , Cytoprotection , Disease Models, Animal , Etanercept , Male , Mice, Inbred C57BL , Mice, Knockout , Myocardial Infarction/genetics , Myocardial Infarction/immunology , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/immunology , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathology , Myocardium/immunology , Myocardium/pathology , Phosphorylation , Receptors, Adiponectin/genetics , Receptors, Adiponectin/metabolism , Receptors, Tumor Necrosis Factor , Time Factors , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism , Up-RegulationABSTRACT
Insulin resistance model of 3T3-L1 adipocytes were prepared with plamotic acid.Adipocytes with generated insulin resistance were cultured with different concentrations of globular domain of adiponectin(gAd:250,500,1 000 ng/ml).The cell culture medium glucose content was detected with the glucose oxidase method,the mRNA expressions of insulin receptor substrate-1 (IRS-1),phosphatidylinositol-3 kinase(PI3K),and protein kinase B(PKB) were detected with real-time quantitative PCR method.The phosphorylation of IRS-1 was detected by Western blot.Compared with the control group,the experimental group showed significantly increased glucose consumption (P ＜ 0.01),and with the increasing gAd concentration,glucose consumption was gradually increasing.IRS-1 phosphorylation was increased gradually with the increasing concentration of gAd.These results suggest that gAd can promote glucose uptake by 3T3-L1 adipocyte model with generated insulin resistance.This may be correlated with promoting insulin signal transduction and improving insulin resistance in adipocytes.
