TY - JOUR
T1 - PPARδ agonist GW501516 prevents uncoupling of endothelial nitric oxide synthase in cerebral microvessels of hph-1 mice
AU - Santhanam, Anantha Vijay R.
AU - D'uscio, Livius V.
AU - He, Tongrong
AU - Katusic, Zvonimir S.
N1 - Funding Information:
This study was funded in part by American Heart Association Scientist Development Grants ( 08-35436N to AVS; 07-30133N to LVD; 09SDG2190046 to TH ), National Institutes of Health Grants ( HL 53524 , HL 91867 to ZSK, and HL111062 ), and the Mayo Foundation . The authors would like to thank Suzanne M. Greiner for assistance with blood cell counts.
PY - 2012/11/5
Y1 - 2012/11/5
N2 - Peroxisome proliferator-activated receptor delta (PPARδ) is ubiquitously expressed in the vasculature, including cerebral circulation. The role of PPARδ in metabolism of tetrahydrobiopterin (BH4) has not been studied in the cerebral microvasculature. In the present study, the effects of PPARδ agonist GW501516 on uncoupling of endothelial nitric oxide synthase (eNOS) were determined in cerebral microvessels of BH 4-deficient hph-1 mice. Wild-type (B6CBA) and hph-1 mice were orally gavaged with a selective PPARδ activator, GW501516 (2 mg/kg/day) for 14 days, and thereafter, cerebral microvessels were isolated and studied. Treatment of hph-1 mice with GW501516 significantly reduced oxidation of BH4 and increased the ratio of BH4 to 7,8-BH2 (P<0.05, n=6-9). Attenuation of L-NAME-inhibitable superoxide anion levels by GW501516 demonstrated that activation of PPARδ might prevent uncoupling of endothelial nitric oxide synthase (eNOS, P<0.05, n=6-9). Western blotting studies demonstrated that GW501516 selectively increased the endothelial expressions of CuZn superoxide dismutase (P<0.05, n=6-9) and catalase (P<0.05, n=6-8). PPARδ activation increased the total nitrite and nitrate (NO2NO3) content in cerebral microvessels (P<0.05, n=6). Obtained results suggest that in vivo activation of PPARδ prevents eNOS uncoupling, restores bioavailability of NO and may help preserve endothelial function in the BH4-deficient cerebral circulation.
AB - Peroxisome proliferator-activated receptor delta (PPARδ) is ubiquitously expressed in the vasculature, including cerebral circulation. The role of PPARδ in metabolism of tetrahydrobiopterin (BH4) has not been studied in the cerebral microvasculature. In the present study, the effects of PPARδ agonist GW501516 on uncoupling of endothelial nitric oxide synthase (eNOS) were determined in cerebral microvessels of BH 4-deficient hph-1 mice. Wild-type (B6CBA) and hph-1 mice were orally gavaged with a selective PPARδ activator, GW501516 (2 mg/kg/day) for 14 days, and thereafter, cerebral microvessels were isolated and studied. Treatment of hph-1 mice with GW501516 significantly reduced oxidation of BH4 and increased the ratio of BH4 to 7,8-BH2 (P<0.05, n=6-9). Attenuation of L-NAME-inhibitable superoxide anion levels by GW501516 demonstrated that activation of PPARδ might prevent uncoupling of endothelial nitric oxide synthase (eNOS, P<0.05, n=6-9). Western blotting studies demonstrated that GW501516 selectively increased the endothelial expressions of CuZn superoxide dismutase (P<0.05, n=6-9) and catalase (P<0.05, n=6-8). PPARδ activation increased the total nitrite and nitrate (NO2NO3) content in cerebral microvessels (P<0.05, n=6). Obtained results suggest that in vivo activation of PPARδ prevents eNOS uncoupling, restores bioavailability of NO and may help preserve endothelial function in the BH4-deficient cerebral circulation.
KW - Antioxidant
KW - Cerebral microvessel
KW - GTP cyclohydrolase I
KW - Nitric oxide
KW - eNOS uncoupling
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U2 - 10.1016/j.brainres.2012.09.012
DO - 10.1016/j.brainres.2012.09.012
M3 - Article
C2 - 22982594
AN - SCOPUS:84867574313
SN - 0006-8993
VL - 1483
SP - 89
EP - 95
JO - Brain Research
JF - Brain Research
ER -