Apoptosis in the left ventricle of chronic volume overload causes endocardial endothelial dysfunction in rats
1 Department of Physiology and Biophysics, 2 Department of Pathology, and 3 Department of Cardiothoracic Surgery, School of Medicine, University of Mississippi Medical Center, Jackson, Mississippi 39216 The hypothesis is that chronic increases in left ventricular (LV) load induce oxidative stress...
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Published in | American journal of physiology. Heart and circulatory physiology Vol. 282; no. 4; pp. H1197 - H1205 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.04.2002
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Subjects | |
Online Access | Get full text |
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Summary: | 1 Department of Physiology and Biophysics,
2 Department of Pathology, and 3 Department of
Cardiothoracic Surgery, School of Medicine, University of
Mississippi Medical Center, Jackson, Mississippi 39216
The
hypothesis is that chronic increases in left ventricular (LV)
load induce oxidative stress and latent matrix metalloproteinase (MMP)
is activated, allowing the heart to dilate in the absence of
endothelial nitric oxide (NO) and thereby reduce filling pressure. To
create volume overload, an arteriovenous (A-V) fistula was placed in
male Sprague-Dawley rats. To decrease oxidative stress and
apoptosis, 0.08 mg/ml nicotinamide (Nic) was administered in
drinking water 2 days before surgery. The rats were divided into the
following groups: 1 ) A-V fistula, 2 ) A-V
fistula + Nic, 3 ) sham operated, 4 )
sham + Nic, and 5 ) control (unoperated); n = 6 rats/group. After 4 wk, hemodynamic parameters
were measured in anesthetized rats. The heart was removed and weighed,
and LV tissue homogeneates were prepared. A-V fistula caused an
increase in heart weight, lung weight, and end-diastolic pressure
compared with the sham group. The levels of malondialdehyde (MDA; a
marker of oxidative stress) was 6.60 ± 0.23 ng/mg protein and NO
was 6.87 ± 1.21 nmol/l in the LV of A-V fistula rats by
spectrophometry. Nic treatment increased NO to 13.88 ± 2.5 nmol/l
and decreased MDA to 3.54 ± 0.34 ng/mg protein ( P = 0.005). Zymographic levels of MMP-2 were increased, as were protein
levels of nitrotyrosine and collagen fragments by Western blot
analysis. The inhibition of oxidative stress by Nic decreased
nitrotyrosine content and MMP activity. The levels of tissue inhibitor
of metalloproteinase-4 mRNA were decreased in A-V fistula rats and
increased in A-V fistula rats treated with Nic by Northern blot
analysis. TdT-mediated dUTP nick-end labeling-positive cells were
increased in A-V fistula rats and decreased in fistula rats treated
with Nic. Acetylcholine and nitroprusside responses in cardiac rings
prepared from the above groups of rats suggest impaired
endothelial-dependent cardiac relaxation. Treatment with Nic improves
cardiac relaxation. The results suggest that an increase in the
oxidative stress and generation of nitrotyrosine are, in part,
responsible for the activation of metalloproteinase and decreased
endocardial endothelial function in chronic LV volume overload.
nitric oxide; malondialdehyde; collagen degradation; tissue
inhibitor of metalloproteinase; arteriovenous fistula; nicotinamide; NADH oxidase; nitrotyrosine; TUNEL; cardiac ring; acetylcholine; nitroprusside; stretch; contraction; relaxation; heart failure |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0363-6135 1522-1539 |
DOI: | 10.1152/ajpheart.00483.2001 |