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Departments of 1 Physiology and Biophysics, 2 Surgery, and 3 Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216; and 4 Case Western Reserve University and University Hospitals and Clinics, Cleveland, Ohio 44106
Collagen degradation is required
for the creation of new integrin binding sites necessary for cell
survival. However, a complete separation between the matrix and the
cell leads to apoptosis, dilatation, and failure. Previous
studies have demonstrated increased metalloproteinase activity in the
failing myocardium. To test the hypothesis that disintegrin
metalloproteinase (DMP) is induced in human heart end-stage failure,
left ventricle tissue from ischemic cardiomyopathic (ICM,
n = 10) and dilated cardiomyopathic (DCM, n = 10) human hearts were obtained at the time of
orthotopic cardiac transplant. Normal (n = 5) tissue
specimens were obtained from unused hearts. The levels of reduced
oxygen species (ROS) were 12 ± 2, 25 ± 3, and 16 ± 2 nmol (means ± SE, P < 0.005) in normal, ICM, and
DCM, respectively, by spectrofluorometry. The percent levels of
endothelial cells were 100 ± 15, 35 ± 19, and 55 ± 11 in normal, ICM, and DCM, respectively, by CD31 labeling. The levels of
nitrotyrosine by Western analysis were significantly increased, and
endothelial nitric oxide (NO) by the Griess method was decreased in ICM
and DCM compared with normal tissue. The synthesis and degradation of
1-integrin and connexin 43 were significantly increased
in ICM and DCM compared with normal hearts by Western analysis. Levels
of DMP were increased, and levels of cardiac inhibitor of
metalloproteinase (CIMP) were decreased. Aggrecanase activity of DMP
was significantly increased in ICM and DCM hearts compared with normal.
These results suggest that the occurrence of cardiomyopathy is
significantly confounded by the increase in ROS, nitrotyrosine, and DMP
activity. This increase is associated with decreased NO, endothelial
cell density, and CIMP. In vitro, treatment of CIMP abrogated the DMP
activity. The treatment with CIMP may prevent degradation of integrin
and connexin and ameliorate heart failure.
nitric oxide; nitrotyrosine; capillary; endocardial; endothelial
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