Disruption of the myocardial extracellular matrix leads to cardiac dysfunction
Henry E. Kim, … , Myron L. Weisfeldt, Jeanine D’Armiento
Henry E. Kim, … , Myron L. Weisfeldt, Jeanine D’Armiento
Published October 1, 2000
Citation Information: J Clin Invest. 2000;106(7):857-866. https://doi.org/10.1172/JCI8040.
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Article

Disruption of the myocardial extracellular matrix leads to cardiac dysfunction

Abstract

MMP activity with disruption of structural collagen has been implicated in the pathophysiology of dilated cardiomyopathy. To examine the role of this enzyme in cardiac function, a transgenic mouse was created that constitutively expressed human collagenase (MMP-1) in the heart. At 6 months of age, these animals demonstrated compensatory myocyte hypertrophy with an increase in the cardiac collagen concentration due to elevated transcription of type III collagen. Chronic myocardial expression of MMP-1 produced loss of cardiac interstitial collagen coincident with a marked deterioration of systolic and diastolic function at 12 months of age. This is the first animal model demonstrating that direct disruption of the extracellular matrix in the heart reproduces the changes observed in the progression of human heart failure.

Authors

Henry E. Kim, Seema S. Dalal, Erik Young, Marianne J. Legato, Myron L. Weisfeldt, Jeanine D’Armiento

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(a) Presence of MMP-1 protein in transgenic mouse hearts. Western blot a...
(a) Presence of MMP-1 protein in transgenic mouse hearts. Western blot analysis was performed on ventricular extracts from 3-month-old transgenic mice (+) and control littermates (–) as described in Methods, and normalized for protein content. Equal amounts of protein were resolved by SDS-PAGE and subject to immunoblotting with anti–MMP-1 polyclonal antibodies. Arrows indicate the active and pro forms of MMP-1. (b) Collagenase activity in the homogenate from the heart of transgenic and control mice. Type I collagen was incubated with homogenate from the heart of a transgenic mouse treated with APMA (TG+) and without APMA (TG–) and the homogenate from the heart of a control littermate treated with APMA (WT+) and without APMA (WT–). As a control, 100 ng of active MMP-1 was incubated with type I collagen (MMP-1). The characteristic collagenase (one-quarter) degradation fragment can be seen only in the APMA-treated homogenate from the transgenic heart (TG+) and the positive control (MMP-1).