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HEART FAILURE

Matrix metalloproteinases and their tissue inhibitors in pressure-overloaded human myocardium during heart failure progression

Victoria Polyakova, PhD^*,*, Stefan Hein, MD, Sawa Kostin, MD^*, Tibor Ziegelhoeffer, MD^* and Jutta Schaper, MD^*

^* Max-Planck-Institute
Kerckhoff-Clinic, Bad Nauheim, Germany

Manuscript received April 13, 2004; revised manuscript received June 17, 2004, accepted July 5, 2004.

^* Reprint requests and correspondence: Dr. Victoria Polyakova, Max-Planck-Institute, Dept. of Experimental Cardiology, Benekestr. 2, D-61231 Bad Nauheim, Germany (Email: v.polyakova{at}kerckhoff.mpg.de).

OBJECTIVES: 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/mm²-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.

Abbreviations and Acronyms   AS = aortic stenosis   ECM = extracellular matrix   EF = ejection fraction   HF = heart failure   IHC = immunohistochemical   LV = left ventricular   MMP = matrix metalloproteinase   PBS = phosphate-buffered saline   TIMP = tissue inhibitor of metalloproteinase   WB = Western blot

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