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Articles in PresS, published online ahead of print November 29, 2001
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00483.2001
Submitted on June 2, 2001
Accepted on November 26, 2001
1 Department of Physiology and Biophysics, The University of Mississippi Medical Center, Jackson, MS, USA
2 Department of Pathology, The University of Mississippi, Jackson, MS, USA
3 Department of Cardiothoracic Surgery School of Medicine, The University of Mississippi, Jackson, MS, USA
* To whom correspondence should be addressed. E-mail: styagi{at}physiology.umsmed.edu.
The hypothesis is that chronic increases in the left ventricle (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, arteriovenous (AV) 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 prior to surgery. The rats were divided into the following groups: 1) AV fistula; 2) AV fistula + Nic; 3) sham operated; 4) sham + Nic; 5) control (unoperated); n=6 in each group. After 4 weeks, hemodynamic parameters were measured in anesthetized rats. Heart was removed, weighed, and LV tissue homogeneates were prepared. AV fistula caused an increase in heart weight, lung weight, and end-diastolic pressure compared to sham group. The levels of malondialdehyde (MDA, a marker of oxidative stress) was 6.60±0.23 ng/mg of protein and NO was 6.87±1.21 nmol/liter in the LV of AV fistula rats by spectrophometry. Nicotinamide treatment increased NO to 13.88±2.5 nmol/liter, and decreased MDA to 3.54±0.34 ng/mg of protein (p=0.005). Zymographic levels of MMP-2 were increased as were protein levels of nitrotyrosine and collagen fragments by Western analysis. The inhibition of oxidative stress by nicotinamide decreased nitrotyrosine content and MMP activity. The levels of TIMP-4 mRNA were decreased in AV fistula and increased in AV fistula rats treated with nicotinamide by Northern analysis. TUNEL positive cells were increased in AV fistula and decreased in fistula rats treated with nicotinamide. Acetylcholine and nitroprusside responses in cardiac rings prepared from above groups of rats suggest impaired endothelial-dependent cardiac relaxation. The treatment with nicotinamide 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.
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