© 2004 European Society of Cardiology
Increased expression of tumor necrosis factor-
converting enzyme and tumor necrosis factor- in peripheral blood mononuclear cells in patients with advanced congestive heart failure
Second Department of Internal Medicine, Iwate Medical University School of Medicine Uchimaru 19-1, Morioka 020-8505, Iwate, Japan
* Corresponding author. Tel.: +81-19-651-5111; Fax: +81-19-651-0401 E-mail address: m_satoh{at}imu.ncvc.go.jp
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Abstract |
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Background: Tumor necrosis factor-
converting enzyme (TACE) has recently been identified as a metalloproteinase-disintegrin, which converts pro-tumor necrosis factor- (TNF-) 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- synthesis in peripheral blood mononuclear cells (PBMC), we analyzed mRNAs and protein-positive cells of both TACE and TNF- 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- mRNAs by real-time RT-PCR, intracellular TACE and TNF- levels by flow cytometry, and TNF- secretion by supernatant ELISA. Levels of TACE and TNF- mRNAs, intracellular TACE and TNF-, and supernatant TNF- were higher in CHF than in controls (P<0.001). There was a positive correlation between TACE and TNF- 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- 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- expression. These observations suggest that TACE in PBMC is an important regulator of TNF- maturation, meaning that TACE may be a potential target for the inhibition of cellular TNF- production in CHF.
Key Words: Flow cytometry • Metalloproteinase • mRNA • Real-time PCR
Received June 27, 2003; Revised December 19, 2003; Accepted February 23, 2004
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