Matrix metalloproteinases and their tissue inhibitors in pressure-overloaded human myocardium during heart failure progression.
OBJECTIVE
We studied the role of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in fibrosis formation in the transition from hypertrophy to heart failure (HF) as well as the cellular source of MMPs and TIMPs.


BACKGROUND
Human pressure-overloaded hearts are characterized by a significant increase in cardiac fibrosis. However, the contribution of the proteolytic/antiproteolytic system in aortic stenosis (AS) during hypertrophy progression has not yet been elucidated.


METHODS
Three groups of AS patients (I: EF >50%, n = 12; II: EF 50% to 30%, n = 10; III: EF <30%, n = 12) undergoing aortic valve replacement and seven controls were studied. Tissue samples were investigated by immunoconfocal microscopy, Western blotting, and zymography.


RESULTS
Quantitative analysis by immunoconfocal microscopy and Western blotting showed an upregulation of MMP-1, -2, -3, -9, -13, and -14 in group I and further increases in later stages. Tissue inhibitors of metalloproteinase-1 and -2 were enhanced and TIMP-4 was decreased in comparison to control. Gelatinolytic activity of MMP-2 significantly (p < 0.05) increased 1.2-fold (group I), 1.5-fold (group II), and 1.6-fold (group III) over control. The level of collagen I was significantly upregulated in all AS groups. Immunoconfocal microscopy showed that MMPs and TIMPs are produced predominantly by fibroblasts. The number of proliferating fibroblasts was significantly elevated during the transition to HF (0.67 n/mm(2)-control, 5.03-group III, p < 0.05).


CONCLUSIONS
In human hearts a continuous turnover of the extracellular matrix occurs during the progression from compensated hypertrophy to HF that is characterized by the upregulation of MMPs and inadequate inhibition by TIMPs. The altered balance between proteolysis/antiproteolysis with accompanying proliferation of fibroblasts results in fibrosis progression.
Dept. of Experimental Cardiology, Max-Planck-Institute, Benekestrasse 2, D-61231 Bad Nauheim, Germany. v.polyakova@kerckhoff.mpg.de
Victoria
V
Polyakova
Stefan
S
Hein
Sawa
S
Kostin
Tibor
T
Ziegelhoeffer
Jutta
J
Schaper
D000368:Aged; D001024:Aortic Valve Stenosis / Q000473:pathology* / Q000601:surgery; D001706:Biopsy; D002455:Cell Division / Q000502:physiology; D018450:Disease Progression; D004699:Endocardium / Q000473:pathology; D004719:Endomyocardial Fibrosis / Q000473:pathology*; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D006333:Heart Failure / Q000473:pathology*; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000473:pathology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism*; D012016:Reference Values; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000502:physiology
D020033:Protein Isoforms; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases