Related Experiment Videos
Peroxisome proliferator ameliorates endothelial dysfunction in a murine model of hyperhomocysteinemia
Harpreet S Sood1, Matthew J Hunt, Suresh C Tyagi
1Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 No. State Street, Jackson, MS 39216-4505, USA.
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.
Insights
High homocysteine (Hcy) levels increase aortic wall stress by elevating nitrotyrosine and matrix metalloproteinase-9 (MMP-9) activity. Ciprofibrate treatment partially mitigates these effects in hyperhomocysteinemia models.
Area of Science:
- Cardiovascular Biology
- Metabolic Disorders
- Pharmacology
Background:
- Hyperhomocysteinemia is linked to endothelial dysfunction.
- Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) antagonism may play a role.
- Nitrotyrosine and matrix metalloproteinase (MMP) activity are implicated in vascular damage.
Purpose of the Study:
- To investigate if increased nitrotyrosine and MMP activity contribute to endothelial dysfunction in hyperhomocysteinemia.
- To examine the role of PPAR-alpha antagonism in this process.
- To assess the impact of hyperhomocysteinemia on aortic wall stress.
Main Methods:
- Cystathionine beta-synthase (CBS) -/+ mice were used to model hyperhomocysteinemia.
- PPAR-alpha was induced using ciprofibrate (CF).
- Plasma homocysteine, aortic nitrotyrosine, MMP activity, blood pressure, and aortic wall stress were measured.
Main Results:
- CBS -/+ mice exhibited significantly elevated plasma homocysteine, aortic nitrotyrosine, and aortic wall stress compared to wild-type mice.
- MMP-9 activity was specifically induced in CBS -/+ mice and reduced by CF treatment.
- Ciprofibrate administration partially normalized elevated parameters in CBS -/+ mice.
Conclusions:
- Elevated homocysteine increases aortic wall stress by enhancing nitrotyrosine and MMP-9 activity.
- PPAR-alpha activation may offer a protective mechanism against hyperhomocysteinemia-induced vascular damage.
- These findings highlight potential therapeutic targets for managing vascular complications of hyperhomocysteinemia.