title: Activated tumour necrosis factor-alpha shedding process is associated with in-hospital complication in patients with acute myocardial infarction.
abstract: TACE [TNF-alpha (tumour necrosis factor-alpha)-converting enzyme] plays an essential role in the shedding of TNF-alpha, which could affect the outcome of AMI (acute myocardial infarction). To investigate the clinical significance of the TACE-TNF-alpha system in AMI, we examined TACE-mediated TNF-alpha synthesis in PBMCs (peripheral blood mononuclear cells), which are a possible source of TNF-alpha in AMI. Forty-one patients with AMI and 15 healthy subjects (HS) were enrolled in the present study. PBMCs were isolated from peripheral blood on day 1 and 14 after the onset of AMI. TACE and TNF-alpha mRNA levels and intracellular median fluorescence intensity were measured by real-time RT (reverse transcriptase)-PCR and flow cytometry respectively. TACE-mediated TNF-alpha production was evaluated in cultured PBMCs with PMA, which is known to activate TACE. Spontaneous TACE and TNF-alpha levels were higher in AMI patients than in HS (P<0.001). TACE and TNF-alpha levels in PMA-stimulated PMBCs were markedly increased in AMI patients compared with HS (P<0.001). There was a positive correlation between TACE and TNF-alpha levels in AMI. Although spontaneous and stimulated levels of TACE and TNF-alpha decreased 14 days after the onset of AMI, levels in AMI patients were higher than in HS. In AMI patients with in-hospital complications (n=15; pump failure in ten, recurrent myocardial infarction in one, malignant ventricular arrhythmia in three and cardiac death in one), spontaneous and stimulated levels of TACE and TNF-alpha were higher than in patients without complications (P<0.01). These levels were higher in AMI patients with in-hospital complications 14 days after onset. These results demonstrate that TACE-mediated TNF-alpha maturation in PBMCs may play an important role in poor outcomes from AMI, suggesting that TACE may be a potential target for the inhibition of cellular TNF-alpha production in AMI.
authors.affiliation: Second Department of Internal Medicine, Iwate Medical University School of Medicine, Uchimaru 19-1, Morioka 020-8505, Iwate, Japan.
authors.forename: Yudai
authors.initials: Y
authors.lastname: Shimoda
authors.forename: Mamoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Tomonari
authors.initials: T
authors.lastname: Akatsu
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hiramori
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000097:blood / Q000209:etiology; D002478:Cells, Cultured; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000209:etiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008666:Metalloendopeptidases / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood* / Q000150:complications; D011379:Prognosis; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013755:Tetradecanoylphorbol Acetate / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D013755:Tetradecanoylphorbol Acetate