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Articles in PresS, published online ahead of print October 25, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00183.2002
Submitted on June 7, 2002
Accepted on October 4, 2002
1 Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
* To whom correspondence should be addressed. E-mail: styagi{at}physiology.umsmed.edu.
To test the hypothesis that endothelial dysfunction in hyperhomocysteinemia (HHcy) was due to increased levels of nitrotyrosine and matrix metalloproteinase (MMP) activity in response of antagonism of peroxisome proliferator activated receptor
(PPAR), cystathionine ß synthase(CBS) -/+ mice were bred, tail tissue was analyzed for genotype by PCR, and tail vein blood was analyzed for homocysteine (Hcy) by spectrofluorometry in 50 male offsprings of 20±3 g at the age of 8 weeks. Mice were separated based on plasma Hcy 4.5±1.5 (+/+, wildtype), and 11.7±3.4 µmoles/liter (-/+), p<0.001 compared with +/+. To induce PPAR, 10 -/+ and 10 +/+ mice were administered with 0.08 mg/ml ciprofibrate (CF) in drinking water for 12 weeks, and grouped: 1) wildtype; 2) wildtype + CF; 3) CBS; 4) CBS + CF (n=6 in each group). In these 4 respective study groups of mice: plasma Hcy was 3.0±0.2, 2.5±1.2, 15.2±2.6 (p<0.05 compared with wildtype), 11.0±2.9 µmoles/liter. Mouse urinary protein was 110±11, 86±6, 179±13, 127±9 µg/day/kg by Bio-Rad dye binding assay. Aortic nitrotyrosine was 0.099±0.012, 0.024±0.004, 0.132±0.024 (p<0.01 compared with wildtype), 0.05±0.01 (scan unit) by Western analysis. MMP-2 activity was 0.053±0.010, 0.024±0.002, 0.039±0.009, 0.017±0.006 (scan unit) by zymography. MMP-9 was specifically induced in CBS -/+ mice, and inhibited by CF treatment. Systolic blood pressure (SP) was 90±2, 88±16, 104±8 (p<0.05 compared with wildtype), 96±3 mmHg. The heart rate was 426±75, 387±63, 466±40, 458±38 beats/min. The aortic wall stress,(SP.radius2/wall thickness)/2.(radius+wall thickness), was 10.2±1.9, 9.7±0.2, 16.6±0.8 (p<0.05 compared with wildtype), 13.1±2.1 dynes/cm2. The results suggested that Hcy increased aortic wall stress by increasing nitrotyrosine and MMP-9 activity. The fibrate reduced MMP-9 in CBS -/+, and MMP-2 activity in both CBS -/+ and wildtype mice. The treatment with fibrate ameliorated endothelial dysfunction in CBS -/+ mice.
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