Increased cardiac mRNA expression of matrix metalloproteinase-1 (MMP-1) and its inhibitor (TIMP-1) in DCM patients.
Left ventricular dilation and myocardial remodeling are hallmarks of dilated cardiomyopathy (DCM). It is assumed that left ventricular dilation is caused by the disintegration of the collagenous network by increased collagenolytic activity of matrix metalloproteinases (MMPs) and their adequate tissue inhibitors (TIMPs). In this study the myocardial MMP-1 and TIMP-1 mRNA expressions were investigated by using real-time quantitative PCR analysis from right septal endomyocardial biopsies of patients with dilated cardiomyopathy (n = 46) and control subjects (n = 11). The volume density (Vv%) of collagen was measured morphometrically. Classification was done according to LV diameters [left ventricular enddiastolic diameter (LVEDD, cm) calculated to body surface area (BSA, m(2))] into three DCM groups: group I (LVEDD-BSA > 2.7-3.0 cm/m(2)), group II ( > 3.0-3.6 cm/m(2)), group III ( > 3.6 cm/m(2)), controls (< 2.7 cm/m(2)). Compared with controls, the MMP-1 expression in patients with DCM was significantly increased (119.2 +/- 45.2 vs. 1.3 +/- 0.4; p < 0.001) as was TIMP-1 expression (9.6 +/- 1.2 vs. 1.3 +/- 0.4; p < 0.01). Moreover the MMP-1 and TIMP-1 expression varied according to LV diameter: group I (MMP-1: 8.7 +/- 3.5; p = 0.33; TIMP- 1: 4.5 +/- 1.2; p < 0.01); group II (MMP-1: 211.4 +/- 86.0; p < 0.001; TIMP-1: 12.5 +/- 1.9 ; p < 0.001); group III (MMP-1: 38.8 +/- 22.6; p < 0.01; TIMP-1: 8.1 +/- 1.7; p < 0.001). Compared with controls, the collagen level in DCMPt. was significantly increased: 5.0 +/- 0.6 vol% vs 1.2 +/- 0.2 vol% p < 0.001 and correlates with LV diameter. This study reveals that the overexpression of MMP-1, which is associated with an increased ratio of MMP-1/TIMP-1 in DCM, indicates an activated collagenolytic system while replacement fibrosis is accumulating. The MMP-1 overexpression is mainly found in moderately dilated DCM hearts (group II) indicating the dynamic process of LV dilation and the importance of collagenases in the early phase of LV remodeling.
Picard
F
F
Department of Cardiology, Angiology and Pneumology, Heinrich-Heine-University Düsseldorf, Germany. picard@uni-duesseldorf.de
Brehm
M
M
Fassbach
M
M
Pelzer
B
B
Scheuring
S
S
Küry
P
P
Strauer
B E
BE
Schwartzkopff
B
B
D015415:Biomarkers / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism*; D004699:Endocardium / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism*; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D020781:Matrix Metalloproteinase 1