Abstract 17094: Activation of Peroxisome Proliferatior-Activated Receptor-delta Prevents Endothelial Dysfunction in Mouse Model of GTP-Cyclohydrolase I Deficiency
Peroxisome proliferatior-activated receptor-delta (PPARδ) is nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPARδ agonists exert vascular protective effects. However, the exact molecular mechanisms underlying the effects of PPARδ on vascular endothelium in-vivo are not understood. In the present study, we used the hph-1 mouse, which displays GTP-cyclohydrolase I (GTPCH I) deficiency leading to uncoupling of endothelial nitric oxide synthase (eNOS). PPARδ agonist GW501516 (2mg/kg/day) was administered by gavage for 14 days in wild-type and hph-1 mice. Superoxide anion production and tetrahydrobiopterin (BH4) levels were measured in the aorta using HPLC. Vascular reactivity of isolated carotid arteries was studied in-vitro. HPLC analysis revealed that BH4 levels were reduced in the aortas of hph-1 mice (4.3±0.5 pmol/mg; P<0.05 vs. wild-type mice: 5.8±0.3 pmol/mg; n=8–9). Consistent with uncoupling of eNOS, L-NAME sensitive production of superoxide anion was significantly increased in the aorta of hph-1 mice (0.91±0.12 nmol 2-hydroxyethidium/mg; P<0.05 vs. wild-type mice: 0.51±0.06 nmol/mg; n=8–9). Consequently, oxidative product of BH4, 7,8-dihydrobiopterin (7,8-BH2), was increased, and endothelium-dependent relaxations to acetylcholine were impaired in carotid arteries of hph-1 mice (P<0.05; n=6–9). Treatment with GW501516 did not affect protein expression and enzymatic activity of GTPCH I. However, GW501516 significantly reduced production of superoxide anion and oxidation of BH4 to 7,8-BH2 in aortas of hph-1 mice (P<0.05; n=7–8). This in turn increased BH4 to 7,8-BH2 ratio (P<0.05; n=7). Furthermore, GW501516 significantly improved endothelium-dependent relaxations to acetylcholine in carotid arteries of hph-1 mice (P<0.05; n=11). Moreover, GW501516 significantly increased protein expression of CuZnSOD in the aortas of hph-1 mice while MnSOD and EC-SOD were unaltered (n=6). Our results demonstrate that in experimental model of eNOS uncoupling GW501516 prevents superoxide anion production and endothelial dysfunction. The vascular protective effects of GW501516 appear to be critically dependent on up-regulation of expression and activity of CuZnSOD.
- © 2010 by American Heart Association, Inc.