Abstract 25: Peroxisome Proliferator Activated Receptor - δ Agonist GW501516 Restores Bioavailability Of Tetrahydrobiopterin And Prevents Cerebral Vascular Dysfunction In Tg2576 Mice Overexpressing Amyloid Precursor Protein

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Anantha Vijay R Santhanam ◽  
Livius V d'Uscio ◽  
Tongrong He ◽  
Pritam Das ◽  
Steven G Younkin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vascular Dysfunction ◽  
Cerebral Arteries ◽  
Superoxide Production ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cerebral Microvessels ◽  
Enos Uncoupling ◽  
Tg2576 Mice ◽  
Cerebral Vascular

Objectives- Oxidative stress and endothelial dysfunction precedes cerebral β-amyloid deposits in human Alzheimer’s disease as well as in transgenic mouse models expressing mutations in amyloid precursor protein (APP). In the present study, we hypothesized that uncoupling of endothelial nitric oxide synthase (eNOS) caused by loss of its essential co-factor, tetrahydrobiopterin (BH 4 ), in cerebral arteries and microvessels contributes, in part, to oxidative stress and cerebral vascular dysfunction in a APP transgenic mouse (Tg2576) that express the Swedish double mutation of human APP. In addition, we examined whether treatment with Peroxisome Proliferator Activated Receptor-δ (PPARδ) activator - GW501516 restores bioavailability of BH 4 and reverses oxidative stress in APP Tg2576 mice. Methods- APP Tg2576 mice (4-5 months old) were treated with GW501516 , a selective PPARδ activator (2 mg/kg/day, po, 14 days). Following treatment, cerebral arteries and microvessels were obtained. Biopterin levels, enzymatic activity of GTP cyclohydrolase I (GTPCH I) and superoxide production were measured by HPLC and protein expression was studied by Western blotting. Results- Cerebral arteries and microvessels demonstrated increased expression of eNOS, while the bioavailability of its essential co-factor BH 4 was significantly reduced, suggestive of eNOS uncoupling in APP Tg2576 mice. Furthermore, expressions of catalase and manganese superoxide dismutase (MnSOD) were decreased, while superoxide production was increased (P<0.01, n=6) in cerebral microvessels of APP Tg2576 mice. Treatment with GW501516 restored the BH 4 /BH 2 ratio in cerebral arteries and microvessels of APP Tg2576 mice (P<0.05, n-7-8), while the enzymatic activity of GTPCH-I remained unchanged (P>0.05, n=6). PPARδ activation also prevented the attenuation in expressions of MnSOD and catalase, and inhibited the increased superoxide production (P<0.05, n=6) in cerebral arteries and microvessels of APP Tg2576 mice. Interestingly, PPARδ activation significantly inhibited the over-expression of APP in cerebral microvessels obtained from APP Tg2576 mice (P<0.001, n=4). Conclusion- Our results suggest that endothelial dysfunction in APP Tg2576 mice may be caused, in part, by reduced bioavailability of BH 4 and uncoupling of eNOS. Treatment of APP Tg2576 mice with PPARδ agonist GW501516 exerted cerebral vascular protection by multiple mechanisms: (a) by inhibiting eNOS uncoupling via increased expressions of MnSOD and catalase, as well as, (b) by attenuating the increased expression of APP in the cerebral microvessels of APP Tg2576 mice.

scholarly journals Endothelium-Specific Interference With Peroxisome Proliferator Activated Receptor Gamma Causes Cerebral Vascular Dysfunction in Response to a High-Fat Diet

2008 ◽  
Vol 103 (6) ◽  
pp. 654-661 ◽  
Author(s):  
Andreas M. Beyer ◽  
Willem J. de Lange ◽  
Carmen M. Halabi ◽  
Mary L. Modrick ◽  
Henry L. Keen ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Vascular Dysfunction ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cerebral Vascular

Abstract W P230: Tetrahydrobiopterin Attenuates Cerebrovascular Oxidative Stress in Tg2576 Mouse Model of Alzheimer’s Disease

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Anantha Vijay R Santhanam ◽  
Livius V d'Uscio ◽  
Zvonimir S Katusic
Keyword(s):  
Oxidative Stress ◽  
Enzymatic Activity ◽  
Superoxide Anion ◽  
Wild Type ◽  
Superoxide Anion Production ◽  
Cerebral Microvessels ◽  
Double Mutation ◽  
Enos Uncoupling ◽  
Anion Production ◽  
Tg2576 Mice

Background: The present study was designed to test the hypothesis that supplementation of tetrahydrobiopterin (BH4) to transgenic mice expressing the Swedish double mutation of human amyloid precursor protein (Tg2576 mice) results in restoration of BH4 levels required for activation of endothelial nitric oxide synthase (eNOS), and in turn, prevents oxidative stress in cerebral microvasculature. Methods: Cerebral microvessels were obtained from 4-5 months old female wild-type and Tg2576 mice. Biopterin levels, enzymatic activity of GTP cyclohydrolase I (GTPCH-I) and superoxide production were measured by HPLC. The effects of supplementation of BH4 on oxidative stress were studied by injecting wild-type and Tg2576 mice subcutaneously with 100 mol/kg (b.w.) of BH 4 ([ 6R ]-5,6,7,8-tetrahydro-L-biopterin dihydrochloride; [ 6R ]-BH4). Results: Enzymatic activity of GTPCH-I, rate limiting enzyme in BH4 biosynthesis, was not different between cerebral microvessels of wild-type and Tg2576 mice. However, bioavailability of BH4, was significantly reduced in cerebral microvessels of Tg2576 mice (P<0.05, n=8). Production of superoxide anions was significantly elevated in cerebral microvessels of Tg2576 mice (P<0.01, n=6), indicative of oxidative stress. This increased superoxide anion production was abolished by L-NAME, a NOS inhibitor, suggestive of eNOS uncoupling (P<0.05, n=6). Supplementation of [ 6R ]-BH4 to wild-type and Tg2576 mice resulted in significant increase in BH4 bioavailability (P<0.05, n=6). Notably, supplementation of [ 6R ]-BH4 abrogated the increase in superoxide anion production in cerebral microvessels of Tg2576 mice (P<0.05, n=5), while superoxide anion production remained unchanged in cerebral microvessels of WT mice. Furthermore, the inhibitory effects of L-NAME on superoxide anion production in cerebral microvessels of Tg2576 mice were abolished following [ 6R ]-BH4 supplementation (P<0.05, n=4). Conclusion: Supplementation of [ 6R ]-BH4 restored bioavailability of BH4, thereby abrogating superoxide anion production derived from eNOS. Our results suggest that uncoupling of eNOS contributes to oxidative stress in cerebral microvessels of Tg2576 mice.

Natural Aldose Reductase Inhibitor: A Potential Therapeutic Agent for Non-alcoholic Fatty Liver Disease

2020 ◽  
Vol 21 (6) ◽  
pp. 599-609 ◽  
Author(s):  
Longxin Qiu ◽  
Chang Guo
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Aldose Reductase ◽  
Fatty Liver Disease ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver

Aldose reductase (AR) has been reported to be involved in the development of nonalcoholic fatty liver disease (NAFLD). Hepatic AR is induced under hyperglycemia condition and converts excess glucose to lipogenic fructose, which contributes in part to the accumulation of fat in the liver cells of diabetes rodents. In addition, the hyperglycemia-induced AR or nutrition-induced AR causes suppression of the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) α and reduced lipolysis in the liver, which also contribute to the development of NAFLD. Moreover, AR induction in non-alcoholic steatohepatitis (NASH) may aggravate oxidative stress and the expression of inflammatory cytokines in the liver. Here, we summarize the knowledge on AR inhibitors of plant origin and review the effect of some plant-derived AR inhibitors on NAFLD/NASH in rodents. Natural AR inhibitors may improve NAFLD at least in part through attenuating oxidative stress and inflammatory cytokine expression. Some of the natural AR inhibitors have been reported to attenuate hepatic steatosis through the regulation of PPARα-mediated fatty acid oxidation. In this review, we propose that the natural AR inhibitors are potential therapeutic agents for NAFLD.

Vascular smooth muscle cell dysfunction in diabetes: nuclear receptors channel to relaxation

2016 ◽  
Vol 130 (20) ◽  
pp. 1837-1839 ◽  
Author(s):  
Geneviève Doyon ◽  
Dennis Bruemmer
Keyword(s):  
Cell Function ◽  
Vascular Dysfunction ◽  
Microvascular Disease ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endothelial Cell Function ◽  
Cell Dysfunction ◽  
Kv Channels ◽  
Voltage Dependent ◽  
Patients With Diabetes

Endothelial dysfunction and impaired vascular relaxation represent a common cause of microvascular disease in patients with diabetes. Although multiple mechanisms underlying altered endothelial cell function in diabetes have been described, there is currently no specific and approved pharmacological treatment. In this edition of Clinical Science, Morales-Cano et al. characterize voltage-dependent K+ (Kv) channels as genes regulated by pharmacological activation of peroxisome proliferator-activated receptor-b/d (PPARb/d). Diabetes altered Kv channel function leading to impaired coronary artery relaxation, which was prevented by pharmacological activation of PPARb/d. These studies highlight an important mechanism of vascular dysfunction in diabetes and point to a potential approach for therapy, particularly considering that PPARb/d ligands have been developed and tested in small clinical trials.

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