Effects of Peroxynitrite on Relaxation through the NO/sGC/cGMP Pathway in Isolated Rat Iliac Arteries

Tawa, Masashi; Shimosato, Takashi; Iwasaki, Hiromichi; Imamura, Teruhiko; Okamura, Tomio

doi:10.1159/000371491

Cited by 20 publications

(18 citation statements)

References 35 publications

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“…Because NO is now recognized to serve as a ligand for sGC but cannot activate the oxidized/heme-free form (Evgenov et al 2006), it is very important to figure out its balance. To overcome this issue, sGC stimulators and sGC activators are used widely as tools for evaluating the redox state of sGC (Evgenov et al 2006;Tawa et al 2014;Tawa et al 2015a,b), and these two types of drugs were also utilized in this study. As a result, relaxation and cGMP formation of endothelium-denuded aortas in response to either the sGC stimulator BAY 41-2272 or the sGC activator BAY 60-2770 were comparable in young and aged mice, suggesting that vascular sGC redox equilibrium is not affected by aging.…”

Section: Discussionmentioning

confidence: 85%

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Aging does not affect soluble guanylate cyclase redox state in mouse aortas

et al. 2016

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Aging is associated with endothelial dysfunction, defined as a reduction in nitric oxide (NO) bioavailability. Although the redox state of the NO acceptor soluble guanylate cyclase (sGC) is another determinant factor for its bioavailability and is disturbed by reactive oxygen species (ROS) known to be increased with age, it is unclear whether aging actually has an impact on vascular sGC redox equilibrium. Therefore, this study investigated this issue using two different types of compounds, the sGC stimulator BAY 41‐2272 and the sGC activator BAY 60‐2770. Plasma thiobarbituric acid‐reactive substances (TBARS) levels were markedly higher in aged (19–20 months old) mice than in young (2–3 months old) mice, whereas superoxide levels in endothelium‐denuded aortas were not different between the groups. The relaxant response of endothelium‐denuded aortas to either BAY 41‐2272 or BAY 60‐2770 was identical in aged and young mice. In addition, the vascular cGMP production stimulated with BAY 41‐2272 or BAY 60‐2770 in aged mice was the same level as that in young mice. These findings suggest that aging accompanied by an increase in systemic oxidative stress does not affect vascular smooth muscle ROS generation and sGC redox equilibrium. Unless ROS are increased in vascular smooth muscle, the sGC redox equilibrium might remain unchanged.

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Section: Discussionmentioning

confidence: 85%

“…A certain type of ROS has been proved to shift vascular sGC from the NO‐sensitive state to the NO‐insensitive state (Stasch et al 2006; Tawa et al. ; Tawa et al. ,b).…”

Section: Discussionmentioning

confidence: 99%

Aging does not affect soluble guanylate cyclase redox state in mouse aortas

et al. 2016

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“…; Tawa et al. ,b, ,b; Goulopoulou et al. ), two different NO‐independent stimulants acting on sGC were used in this study as valuable tools for indirectly assessing the redox state of the enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…) and iliac arteries (Tawa et al. , ) or in cultured sheep pulmonary artery smooth muscle cells (Zhou et al. ).…”

Section: Introductionmentioning

confidence: 99%

Soluble guanylate cyclase redox state under oxidative stress conditions in isolated monkey coronary arteries

Tawa

Okamura

2016

Pharmacology Res & Perspec

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Coronary artery disease is associated with oxidative stress due to the excessive generation of free radicals in the vascular wall. This study investigated the impact of tert‐butyl hydroperoxide (t‐BuOOH), a peroxyl radical generator, on the redox state of soluble guanylate cyclase (sGC) in isolated monkey coronary arteries. Helically cut strips of endothelium‐intact monkey coronary arteries treated with the nitric oxide synthase inhibitor NG‐nitro‐L‐arginine (10 μmol/L) were exposed for approximately 60 min to either no drug or t‐BuOOH (100 μmol/L) in the presence and absence of α‐tocopherol (300 μmol/L). Relaxation and cGMP levels in response to the sGC stimulator BAY 41‐2272 and the sGC activator BAY 60‐2770 were assessed by organ chamber technique and enzyme immunoassay, respectively. The relaxant response to BAY 41‐2272 was significantly impaired by the exposure to t‐BuOOH, whereas the response to BAY 60‐2770 was significantly augmented. In addition, vascular cGMP accumulation caused by BAY 41‐2272 was decreased by the exposure to t‐BuOOH, whereas for BAY 60‐2770, it was increased. These effects of t‐BuOOH were abolished by coincubation with α‐tocopherol. Furthermore, correlations were observed between BAY compound‐induced relaxant magnitudes and cGMP levels. Therefore, it is concluded that increased oxidative stress leads to disruption of the sGC redox state in monkey coronary arteries. This finding is of great importance for understanding coronary physiology in primates.

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“…Peroxynitrite is a mediator of the oxidation of tetrahydrobiopterin; and it can also inhibit a key target of NO bioactivity, soluble guanylate cyclase (sGC), by oxidizing the ferrous iron in its attached heme group [120,121,122,123]. Oxidized sGC is not only unresponsive to NO, but it also is prone to lose its heme group, leading to its proteasomal degradation.…”

Section: High-dose Folate Combats Enos Uncouplingmentioning

confidence: 99%

Supplementation with Phycocyanobilin, Citrulline, Taurine, and Supranutritional Doses of Folic Acid and Biotin—Potential for Preventing or Slowing the Progression of Diabetic Complications

McCarty

2017

Healthcare

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Oxidative stress, the resulting uncoupling of endothelial nitric oxide synthase (eNOS), and loss of nitric oxide (NO) bioactivity, are key mediators of the vascular and microvascular complications of diabetes. Much of this oxidative stress arises from up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Phycocyanobilin (PhyCB), the light-harvesting chromophore in edible cyanobacteria such as spirulina, is a biliverdin derivative that shares the ability of free bilirubin to inhibit certain isoforms of NADPH oxidase. Epidemiological studies reveal that diabetics with relatively elevated serum bilirubin are less likely to develop coronary disease or microvascular complications; this may reflect the ability of bilirubin to ward off these complications via inhibition of NADPH oxidase. Oral PhyCB may likewise have potential in this regard, and has been shown to protect diabetic mice from glomerulosclerosis. With respect to oxidant-mediated uncoupling of eNOS, high-dose folate can help to reverse this by modulating the oxidation status of the eNOS cofactor tetrahydrobiopterin (BH4). Oxidation of BH4 yields dihydrobiopterin (BH2), which competes with BH4 for binding to eNOS and promotes its uncoupling. The reduced intracellular metabolites of folate have versatile oxidant-scavenging activity that can prevent oxidation of BH4; concurrently, these metabolites promote induction of dihydrofolate reductase, which functions to reconvert BH2 to BH4, and hence alleviate the uncoupling of eNOS. The arginine metabolite asymmetric dimethylarginine (ADMA), typically elevated in diabetics, also uncouples eNOS by competitively inhibiting binding of arginine to eNOS; this effect is exacerbated by the increased expression of arginase that accompanies diabetes. These effects can be countered via supplementation with citrulline, which efficiently enhances tissue levels of arginine. With respect to the loss of NO bioactivity that contributes to diabetic complications, high dose biotin has the potential to “pinch hit” for diminished NO by direct activation of soluble guanylate cyclase (sGC). High-dose biotin also may aid glycemic control via modulatory effects on enzyme induction in hepatocytes and pancreatic beta cells. Taurine, which suppresses diabetic complications in rodents, has the potential to reverse the inactivating impact of oxidative stress on sGC by boosting synthesis of hydrogen sulfide. Hence, it is proposed that concurrent administration of PhyCB, citrulline, taurine, and supranutritional doses of folate and biotin may have considerable potential for prevention and control of diabetic complications. Such a regimen could also be complemented with antioxidants such as lipoic acid, N-acetylcysteine, and melatonin—that boost cellular expression of antioxidant enzymes and glutathione—as well as astaxanthin, zinc, and glycine. The development of appropriate functional foods might make it feasible for patients to use complex nutraceutical regimens of the sort suggested here.

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Effects of Peroxynitrite on Relaxation through the NO/sGC/cGMP Pathway in Isolated Rat Iliac Arteries

Cited by 20 publications

References 35 publications

Aging does not affect soluble guanylate cyclase redox state in mouse aortas

Aging does not affect soluble guanylate cyclase redox state in mouse aortas

Soluble guanylate cyclase redox state under oxidative stress conditions in isolated monkey coronary arteries

Supplementation with Phycocyanobilin, Citrulline, Taurine, and Supranutritional Doses of Folic Acid and Biotin—Potential for Preventing or Slowing the Progression of Diabetic Complications

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