title: Peroxisome proliferator ameliorates endothelial dysfunction in a murine model of hyperhomocysteinemia.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 No. State Street, Jackson, MS 39216-4505, USA.
authors.forename: Harpreet S
authors.initials: HS
authors.lastname: Sood
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hunt
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: 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
chemical_list: 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