Cv. Thomas et al., INCREASED MATRIX METALLOPROTEINASE ACTIVITY AND SELECTIVE UP-REGULATION IN LV MYOCARDIUM FROM PATIENTS WITH END-STAGE DILATED CARDIOMYOPATHY, Circulation, 97(17), 1998, pp. 1708-1715
Citations number
45
Categorie Soggetti
Peripheal Vascular Diseas",Hematology,"Cardiac & Cardiovascular System
Background-One of the hallmarks of dilated cardiomyopathy (DCM) is lef
t ventricular (LV) remodeling. The matrix metalloproteinases (MMPs) ar
e a family of enzymes that contribute to extracellular remodeling in s
everal disease states. Additionally, a family of inhibitors called tis
sue 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 activi
ty remain unexplored. Methods and Results-Relative LV myocardial MMP a
ctivity was determined in the normal (n=8) and idiopathic DCM (n=7) hu
man LV myocardium by substrate zymography. Relative LV myocardial abun
dance 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 zymograph
ic activity increased with DCM compared with normal (984+/-149 versus
413+/-64 pixels, P<.05). With DCM, LV myocardial abundance of MMP-1 de
creased 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 compar
ed with normal. LV myocardial abundance of TIMP-1 and TIMP-2 increased
by >500% with DCM. A high-molecular-weight immunoreactive band for bo
th TIMP-1 and TIMP-2, suggesting a TIMP/MMP complex, was increased >60
0% with DCM. Conclusions-This study demonstrated increased LV myocardi
al MMP activity and evidence for independent regulatory mechanisms of
MMP and TIMP expression with DCM. These findings suggest that selectiv
e inhibition of MMP species within the LV myocardium may provide a nov
el therapeutic target in patients with DCM.