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Increased expression of tumor necrosis factor‐α converting enzyme and tumor necrosis factor‐α in peripheral blood mononuclear cells in patients with advanced congestive heart failure
Author(s) -
Satoh Mamoru,
Iwasaka Junji,
Nakamura Motoyuki,
Akatsu Tomonari,
Shimoda Yudai,
Hiramori Katsuhiko
Publication year - 2004
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1016/j.ejheart.2004.02.007
Subject(s) - peripheral blood mononuclear cell , tumor necrosis factor alpha , heart failure , medicine , ionomycin , intracellular , pathogenesis , endocrinology , biology , calcium , biochemistry , in vitro , microbiology and biotechnology
Background: Tumor necrosis factor‐α converting enzyme (TACE) has recently been identified as a metalloproteinase‐disintegrin, which converts pro‐tumor necrosis factor‐α (TNF‐α) to the mature form, and is an important mediator in the pathogenesis of CHF. Aims: In order to establish the importance of TACE in the regulation of TNF‐α synthesis in peripheral blood mononuclear cells (PBMC), we analyzed mRNAs and protein‐positive cells of both TACE and TNF‐α in PBMC obtained from patients with congestive heart failure (CHF). Methods and results: PBMC were obtained from 46 patients with CHF and 22 controls. PBMC were activated by phorbol 12‐myristate 13‐acetate and ionomycin and assessed for TACE and TNF‐α mRNAs by real‐time RT‐PCR, intracellular TACE and TNF‐α levels by flow cytometry, and TNF‐α secretion by supernatant ELISA. Levels of TACE and TNF‐α mRNAs, intracellular TACE and TNF‐α, and supernatant TNF‐α were higher in CHF than in controls ( P <0.001). There was a positive correlation between TACE and TNF‐α levels in CHF patients (mRNA: r =0.60, P <0.001, intracellular protein levels: r =0.76, P <0.001). When the CHF group was divided into two subgroups by NYHA functional class (I and II vs. III and IV), levels of TACE and TNF‐α were significantly higher in severe CHF patients (NYHA III or IV) than in mild CHF patients (NYHA I or II) (mRNA: P <0.001; intracellular protein levels: P <0.001). Conclusion: These results demonstrate that in patients with CHF, and especially those with severe CHF, TACE expression in PBMC increases with TNF‐α expression. These observations suggest that TACE in PBMC is an important regulator of TNF‐α maturation, meaning that TACE may be a potential target for the inhibition of cellular TNF‐α production in CHF.