Tumor necrosis factor-alpha-converting enzyme and tumor necrosis factor-alpha in human dilated cardiomyopathy.
BACKGROUND
Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). TNF-alpha-converting enzyme (TACE) has recently been purified and its complementary DNA cloned. The expression of TACE results in the production of a functional enzyme that has precursor TNF-alpha in the mature form. The aim of this study was to determine whether TACE is expressed with TNF-alpha in myocardium and whether levels of TACE and TNF-alpha are related to clinical severity of DCM.


RESULTS
Endomyocardial tissues were obtained from 30 patients with DCM and 5 control subjects. TNF-alpha and TACE mRNA levels were measured by a novel real-time quantitative reverse transcriptase-polymerase chain reaction method. Expression of TNF-alpha and TACE proteins was determined by immunohistochemical analysis. TNF-alpha mRNA was expressed in DCM patients (TNF-alpha/GAPDH ratio 0.85+/-0.24) but not in control subjects. TACE mRNA expression was significantly greater in DCM patients than in control subjects (TACE/GAPDH ratio 2.52+/-0.59 vs 0.03+/-0.02, P<0.05). A positive correlation was found between TNF-alpha and TACE mRNA levels (r=0.779, P<0.001). TACE and TNF-alpha immunostaining was observed in myocytes in patients with DCM. When 2 subgroups of DCM were divided on the basis of left ventricular end-systolic diameter (LVESD) of 45 mm and left ventricular ejection fraction (LVEF) of 40%, the DCM subgroup with high LVESD (>/=45 mm) showed significantly greater expression of TACE (P=0.02) and TNF-alpha (P=0. 001) than did the low LVESD subgroup (<45 mm). In addition, the DCM subgroup with lower LVEF (<40%) showed higher expression of TACE (P=0.006) and TNF-alpha (P=0.01) than did the subgroup with high LVEF (>/=40%).


CONCLUSIONS
This study has shown that increased myocardial TACE expression is associated with elevated myocardial TNF-alpha expression in both mRNA and protein levels in clinically advanced DCM.
Satoh
M
M
Second Department of Internal Medicine, Iwate Medical University School of Medicine, Iwate, Japan. staohm@iwate-med.ac.jp
Nakamura
M
M
Saitoh
H
H
Satoh
H
H
Maesawa
C
C
Segawa
I
I
Tashiro
A
A
Hiramori
K
K
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000293:Adolescent; D000328:Adult; D000368:Aged; D002311:Cardiomyopathy, Dilated / Q000097:blood* / Q000201:enzymology; D017931:DNA Primers; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008666:Metalloendopeptidases / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human