Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension

Landmesser, Ulf; Dikalov, Sergey; Price, S. Russ; McCann, Louise; Fukai, Tohru; Holland, Steven M.; Mitch, William E.; Harrison, David G.

doi:10.1172/jci14172

Cited by 683 publications

(692 citation statements)

References 64 publications

Supporting

Mentioning

659

Contrasting

Unclassified

Order By: Relevance

“…51 Endothelial NO synthase (eNOS) uncoupling is also a characteristic feature of accelerated vascular aging in diabetes mellitus, hypertension and is induced by oxidation of tetrahydrobiopterin and loss of this important eNOS cofactor. 52 This process is initiated by O 2 -. from Nox enzymes or mitochondrial oxidases and is, in part, regulated by cytokines from inflammatory monocytes, 53 as discussed below.…”

mentioning

confidence: 99%

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

2017

View full text Add to dashboard Cite

Figure.Central role of oxidative stress in accelerated vascular aging in hypertension. AT1R indicates angiotensin II receptor type 1; BH 2 , dihydrobiopterin; BH 4 , tetrahydrobiopterin; BMP, bone morphogenic protein; CypD, cyclophilin D; eNOS, endothelial NO synthase; ET1R, endothelin 1 receptor; H 2 O 2 , hydrogen peroxide; MMP, matrix metalloproteinase; Nox, NADPH oxidase; O 2 −. , superoxide anion; RANTES, regulated on activation, normal T cell expressed and secreted chemokine; and SmgGDS, GTP-binding protein dissociation stimulator. by guest on

show abstract

mentioning

confidence: 99%

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

2017

View full text Add to dashboard Cite

show abstract

“…7,21,23 Decrease in NO production caused by endothelial dysfunction can lead to an early sign of various cardiovascular diseases such as atherosclerosis. 6,11 Inflammation has an important role in the process of atherosclerosis plaque growth until thrombosis occurs that is caused by rupture. 9,25,26 Macrophage located in the plaque contributes to the atherosclerosis occurrence by activating NF-κB to stimulate proinflammatory genes production.…”

Section: Discussionmentioning

confidence: 99%

“…It can happen due to superoxide anion (O 2 -) which is one of the very reactive free radicals type that binds directly to NO and performs peroxynitric. 11 Besides that, oxidative stress causes tetrahidropbiopterin (BH4) oxidation as one of the NO synthetic cofactor. This oxidation causes endothelial nitric oxide synthase (eNOS) uncoupling and results in the decrease of eNOS expression and NO production.…”

Section: Introductionmentioning

confidence: 99%

Effects of quercetin on the nicotine-induced oxidative status in male Wistar rats: study on c-reactive protein (CRP) and malondialdehyde (MDA) concentrations

2016

View full text Add to dashboard Cite

Nicotine can cause atherosclerosis by activating nuclear factor-kB (NF-kB) pathway lead to induce proinflammatory cytokines release as C-reactive protein (CRP) main regulators. The increase of CRP can induce reactive oxygen species (ROS) and increase of malondialdehyde (MDA). Quercetin has been proven to have antiinflammatory and antioxidant effects. This study was conducted to evaluate effect of quercetin on serum CRP and MDA concentrations in rats induced by nicotine. This was a true experimental study with post test only control group design. Thirty six of male Wistar rats were divided into six groups. Group I as normal control received 1 mL/kg BW of NaCl 0.9% solution. Group II as negative control received 2 mg/kg BW of nicotine and Group III as positive control received 2 mg/kg BW of nicotine and atorvastatin at dose of 5 mg/kg BW. Group IV-VI as treatment groups received 2 mg/kg BW of nicotine and quercetin at dose of 25; 50 or 100 mg/kg BW, respectively. Nicotine was given subcutaneously whereas atorvastatin and quercetin were given orally once per day for 28 days, consecutively. Serum CRP and MDA concentrations were measured using Rat hs-CRP ELISA kit and TBARS assay kit, respectively. Data were analyzed using analysis of variance (ANOVA) continued using LSD post-hoc test. The results showed that quercetin reduced serum CRP and MDA concentrations in dose dependent manner. Serum CRP concentration on Group V (173.39 ± 34.85 ng/mL) and Group VI (114.15 ± 43.62 ng/mL) were significantly lower than that Group II (244.77 ± 37.95 ng/mL) (p<0.05). Furthermore, serum MDA concentration on Group IV (5.95 ± 0.11 mmol/mL), Group V (3.93 ± 0.09 mmol/mL) and Group VI (2.14 ± 0.09 mmol/mL) were significantly lower than that Group II (7.29 ± 0.06 mmol/mL) (p<0.05). In conclusion, quercetin reduces the nicotine-induced oxidative status in rats. ABSTRAKNikotin dapat menyebabkan atherosclerosis dengan mengaktifkan jalur nuclear factorkB (NF-kB) yang menginduksi pelepasan sitokin proinflamasi sebagai regulator utama C-reactive protein (CRP). Kenaikan CRP dapat menginduksi reactive oxygen species (ROS) dan meningkatkan malondialdehid (MDA). Quersetin terbukti memiliki efek antiinflamasi J Med Sci, Volume 48, No. 2, 2016 April: 81-88 82 dan antioksisdan. Penelitian ini dilakukan untuk mengkaji efek quersetin terhadap kadar serum CRP dan MDA tikus yang diinduksi nikotin. Penelitian ini merupakan penelitian eksprimental murni menggunakan rancangan post test only control. Tiga puluh enam ekor tikus dibagi menjadi enam kelompok. Kelompok I sebagai control normal mnerima larutan NaCl 0.9% 1 ml/kg BB. Kelompok II sebagai control negatif menerima nikotik 2 mg/kg BB. Kelompok III sebagai control positif menerima nikotin 2 mg/kg BB dan atorvastatin 5 mg/kg BB. Kelompok IV-VI sebagai kelompok perlakuan menerima nikotin 2 mg/kg BB dan quersetin berturut-turut 25; 50 dan 100 mg/kg BB. Nikotin diberikan secara subkutan sedangkan atorvastatin dan quersetin diberikan secara oral. Kadar CRP dan MDA serum ditetapkan menggunakan Rat ...

show abstract

“…Restoring BH 4 level through subsequent dosing has reduced the symptoms of endothelial dysfunction in chronic smokers and patients with diabetes (Pieper et al, 1995;Shinozaki et al, 2000), hypercholesterolemia (Stroes et al, 1997) or ischemia-reperfusion injury (Tiefenbacher et al, 1996). Treatment of deoxycorticosterone acetate salt induced mice with oral BH 4 attenuated vascular reactive oxygen species production, increased NO levels and blunted hypertension compared with non-hypertensive control mice (Landmesser et al, 2003). Besides supplementing BH 4 , cells exposed to antioxidants such as Glutathione, Vitamin C or E (which are capable of providing chemical stabilization to BH 4 ), preventing BH 4 oxidation and increases cellular eNOS activity (Wolff et al, 1993;Yoshida et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

DIHYDROBIOPTERIN (BH<sub>2</sub>): KEY DETERMINANT IN INFLUENCING ARGININE MEDIATED ENDOTHELIAL TOLERANCE AND DYSFUNCTION

Mohan¹,

Patel²,

Bolinaga³

et al. 2012

American Journal of Biochemistry and Biotechnology

View full text Add to dashboard Cite

The redox-sensitive tetrahydrobiopterin (BH 4 ) is an essential cofactor that is required by endothelial Nitric Oxide Synthase (eNOS) for L-arginine (ARG) mediated Nitric Oxide (NO) generation. Oxidation of BH 4 causes cofactor insufficiency and uncoupling of eNOS, resulting in product switching from NO to O 2•¯ production. Here we tested the hypothesis that eNOS uncoupling is not simply a consequence of BH 4 insufficiency, but rather results from a diminished ratio of BH 4 versus its catalytically incompetent oxidation product, 7,8-dihydrobiopterin (BH 2 ). Human Umbilical Vein Endothelial Cells (HUVEC) were incubated for 2 h in Locke's buffer with 100 µM ARG with or without other agents for 2 h (acute) or in medium for 7 days and challenged in buffer for 2 h (chronic). eNOS activity was determined by cellular accumulation of nitrite/nitrate and its expression was measured using ELISA method. Dihydroethidium fluorescence technique was used to measure O 2•¯ accumulation. For binding studies, cell extracts were quantified for levels of BH 4 , BH 2 , quinonoid isoform of BH 2 (qBH 2 ) and biopterin using a modified HPLC method. [3 H]BH 4 binding studies revealed BH 4 and BH 2 bind eNOS with equal affinity and BH 2 can efficiently replace BH 4 in preformed eNOS-BH 4 complexes. While the total pterin pool of HUVEC was unaffected by chronic (7 days) exposure to ARG, BH 2 levels increased from undetectable to 40% of total pterin. This BH 2 accumulation was associated with diminished NO activity and accelerated O 2 •¯ production. Reciprocally, O 2•¯ production was found to negatively correlate with intracellular ratio of BH 4 -to-BH 2 . Our findings implicate intracellular BH 4 -to-BH 2 ratio, not simply BH 4 amount, as a critical in vitro determinant of eNOS product formation during continuous ARG supplementation. Accordingly, diminished ratio of BH 4 -to-BH 2 is likely to be the fundamental molecular link between oxidative stress and endothelial dysfunction during ARG mediated tolerance development.

show abstract

Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension

Cited by 683 publications

References 64 publications

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

Effects of quercetin on the nicotine-induced oxidative status in male Wistar rats: study on c-reactive protein (CRP) and malondialdehyde (MDA) concentrations

DIHYDROBIOPTERIN (BH<sub>2</sub>): KEY DETERMINANT IN INFLUENCING ARGININE MEDIATED ENDOTHELIAL TOLERANCE AND DYSFUNCTION

Contact Info

Product

Resources

About