Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy.
BACKGROUND
One of the hallmarks of dilated cardiomyopathy (DCM) is left ventricular (LV) remodeling. The matrix metalloproteinases (MMPs) are a family of enzymes that contribute to extracellular remodeling in several disease states. Additionally, a family of inhibitors called tissue inhibitors of MMPs (TIMPs) has been shown to exist and to tightly regulate MMP activity. However, the types of MMPs and TIMPs expressed within the normal and DCM LV myocardium and the relation to MMP activity remain unexplored.


RESULTS
Relative LV myocardial MMP activity was determined in the normal (n=8) and idiopathic DCM (n=7) human LV myocardium by substrate zymography. Relative LV myocardial abundance of interstitial collagenase (MMP-1), stromelysin (MMP-3), 72 kD gelatinase (MMP-2), 92 kD gelatinase (MMP-9), TIMP-1, and TIMP-2 were measured with quantitative immunoblotting. LV myocardial MMP zymographic activity increased with DCM compared with normal (984+/-149 versus 413+/-64 pixels, P<.05). With DCM, LV myocardial abundance of MMP-1 decreased to 16+/-6% (P<.05), MMP-3 increased to 563+/-212% (P<.05), MMP-9 increased to 422+/-64% (P<.05), and MMP-2 was unchanged when compared with normal. LV myocardial abundance of TIMP-1 and TIMP-2 increased by >500% with DCM. A high-molecular-weight immunoreactive band for both TIMP-1 and TIMP-2, suggesting a TIMP/MMP complex, was increased >600% with DCM.


CONCLUSIONS
This study demonstrated increased LV myocardial MMP activity and evidence for independent regulatory mechanisms of MMP and TIMP expression with DCM. These findings suggest that selective inhibition of MMP species within the LV myocardium may provide a novel therapeutic target in patients with DCM.
Thomas
C V
CV
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.
Coker
M L
ML
Zellner
J L
JL
Handy
J R
JR
Crumbley
A J
AJ
Spinale
F G
FG
D000293:Adolescent; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000201:enzymology*; D002648:Child; D017364:Collagenases / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism*; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D015854:Up-Regulation
D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1