Peroxisome proliferator ameliorates endothelial dysfunction in a murine model of hyperhomocysteinemia.
To test the hypothesis that endothelial dysfunction in hyperhomocysteinemia was due to increased levels of nitrotyrosine and matrix metalloproteinase (MMP) activity in response to antagonism of peroxisome proliferator-activated receptor-alpha (PPAR-alpha), cystathionine beta-synthase (CBS) -/+ mice were bred, tail tissue was analyzed for genotype by PCR, and tail vein blood was analyzed for homocysteine (Hcy) by spectrofluorometry. To induce PPAR-alpha, mice were administered 8 microg/ml of ciprofibrate (CF) and grouped: 1) wild type (WT), 2) WT + CF, 3) CBS, 4) CBS + CF (n = 6 in each group). In these four groups of mice, plasma Hcy was 3.0 +/- 0.2, 2.5 +/- 1.2, 15.2 +/- 2.6 (P < 0.05 compared with WT), 11.0 +/- 2.9 micromol/l. Mouse urinary protein was 110 +/- 11, 86 +/- 6, 179 +/- 13, 127 +/- 9 microg.day(-1). kg(-1) 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 WT), 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 (SPB) was 90 +/- 2, 88 +/- 16, 104 +/- 8 (P < 0.05 compared with WT), 96 +/- 3 mmHg. Aortic wall stress [(SPB. radius(2)/wall thickness)/2(radius + wall thickness)] was 10.2 +/- 1.9, 9.7 +/- 0.2, 16.6 +/- 0.8 (P < 0.05 compared with WT), 13.1 +/- 2.1 dyn/cm(2). The results suggest that Hcy increased aortic wall stress by increasing nitrotyrosine and MMP-9 activity.
Sood
Harpreet S
HS
Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 No. State Street, Jackson, MS 39216-4505, USA.
Hunt
Matthew J
MJ
Tyagi
Suresh C
SC
D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D003541:Cystathionine beta-Synthase / Q000235:genetics; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004789:Enzyme Activation; D058607:Fibric Acids; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000235:genetics; D020025:Peroxisome Proliferators / Q000378:metabolism*; D010641:Phenotype; D011507:Proteinuria / Q000209:etiology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis
D058607:Fibric Acids; D061965:Matrix Metalloproteinase Inhibitors; D020025:Peroxisome Proliferators; D006710:Homocysteine; C002744:3-nitrotyrosine; D014443:Tyrosine; D002995:Clofibric Acid; D020782:Matrix Metalloproteinases; D003541:Cystathionine beta-Synthase; C019304:ciprofibrate