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Am J Physiol Lung Cell Mol Physiol 283: L239-L245, 2002; doi:10.1152/ajplung.00001.2002
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Vol. 283, Issue 2, L239-L245, August 2002

TRANSLATIONAL PHYSIOLOGY
Induction of oxidative stress and disintegrin metalloproteinase in human heart end-stage failure

Matthew J. Hunt1, Giorgio M. Aru2, Melvin R. Hayden1, Charles K. Moore3, Brian D. Hoit4, and Suresh C. Tyagi1

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 beta 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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