Various intracellular compartments cooperate in the release of nitric oxide from glycerol trinitrate in liver

Kozlov, Andrey V.; Dietrich, Barbara; Nohl, Hans

doi:10.1038/sj.bjp.0705323

Cited by 60 publications

(43 citation statements)

References 35 publications

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“…At least in the liver, our combined inhibitor and cell-fractionation studies suggest that hepatic NO 2 Ϫ reductase activity occurs in the cytosol, the mitochondrion (along the ETC), and, predominantly, the microsomes (Cyt P 450 ), with thiols and metalloproteins playing a crucial cooperative role. Microsomal heme-containing cytochromes are effective NO 2 Ϫ reductases (36,37), as confirmed by the spectral studies herein.…”

Section: Discussionsupporting

confidence: 53%

Tissue Processing of Nitrite in Hypoxia

Feelisch

Fernandez

Bryan

et al. 2008

Journal of Biological Chemistry

194

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Although nitrite (NO 2؊ ) and nitrate (NO 3 ؊ ) have been considered traditionally inert byproducts of nitric oxide (NO) metabolism, recent studies indicate that NO 2 ؊ represents an important source of NO for processes ranging from angiogenesis through hypoxic vasodilation to ischemic organ protection. Despite intense investigation, the mechanisms through which NO 2 ؊ exerts its physiological/pharmacological effects remain incompletely understood. We sought to systematically investigate the fate of NO 2 ؊ in hypoxia from cellular uptake in vitro to tissue utilization in vivo using the Wistar rat as a mammalian model. We find that most tissues (except erythrocytes) produce free NO at rates that are maximal under hypoxia and that correlate robustly with each tissue's capacity for mitochondrial oxygen consumption. By comparing the kinetics of NO release before and after ferricyanide addition in tissue homogenates to mathematical models of NO 2 ؊ reduction/NO scavenging, we show that the amount of nitrosylated products formed greatly exceeds what can be accounted for by NO trapping. This difference suggests that such products are formed directly from NO 2 ؊ , without passing through the intermediacy of free NO. Inhibitor and subcellular fractionation studies indicate that NO 2 ؊ reductase activity involves multiple redundant enzymatic systems (i.e. heme, iron-sulfur cluster, and molybdenumbased reductases) distributed throughout different cellular compartments and acting in concert to elicit NO signaling. These observations hint at conserved roles for the NO 2 ؊ -NO pool in cellular processes such as oxygen-sensing and oxygen-dependent modulation of intermediary metabolism. Nitric oxide (NO)3 is the archetypal effector of redox-regulated signal transduction throughout phylogeny, from microorganisms to plants and animals (1). The conserved influences of NO extend from the regulation of basic cellular processes such as intermediary metabolism (2), cellular proliferation (3), and apoptosis (4) to systemic processes such as hypoxic vasoregulation (5). Mammalian NO production has been attributed to the enzymatic activity of NO synthases, nitrate (NO 3 Ϫ )/nitrite (NO 2 Ϫ ) reductases and non-enzymatic NO 2 Ϫ reduction (6). The NO produced is believed to act directly as a signaling molecule by binding to the heme of soluble guanylyl cyclase or nitrosating peptide/protein cysteine residues (7). More recently, it has become apparent that NO 2 Ϫ , previously considered an inert byproduct of NO metabolism present in plasma (50 -500 nM) and tissues (0.5-25 M), is, under some conditions, also a source of NO/nitrosothiol signaling (6,8). Although the importance of NO 2 Ϫ has received increasing appreciation (9) as being central to processes including exercise (10), hypoxic vasodilation (11), myocardial preconditioning (12, 13), and angiogenesis (14), controversy surrounds the chemistry, kinetics, and tissue specificity of NO 2 Ϫ bioactivity (15, 16). Perhaps the greatest uncertainty pertains to the role of heme moieties in NO 2...

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Section: Discussionsupporting

confidence: 53%

Tissue Processing of Nitrite in Hypoxia

Feelisch

Fernandez

Bryan

et al. 2008

Journal of Biological Chemistry

194

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“…This may help to explain the efficacy of GTN in some patients despite their genetic ALDH2 deficiency. According to the results of functional studies as well as previous reports, the catalytic efficiency of ALDH2 is much higher than that of these other enzymes, which have been shown to perform the same function during GTN biotransformation (27). From the standpoint of NO biology, mitochondrial GTN reductase activity is significantly greater than mitochondrial NO synthase activity (28,29).…”

Section: Discussionmentioning

confidence: 80%

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin

Zhang

Jin³

et al. 2006

Journal of Clinical Investigation

144

101

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Glyceryl trinitrate (GTN), also known as nitroglycerin, has been used to treat angina and heart failure for more than 130 years. Recently, it was shown that mitochondrial aldehyde dehydrogenase-2 (ALDH2) is responsible for formation of NO, the metabolite needed for GTN efficacy. In the present study, we show that the common G-to-A polymorphism in exon 12 of ALDH2 -resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes -is associated with a lack of efficacy of sublingual GTN in Chinese subjects. We also show that the catalytic efficiency (V max /K m ) of GTN metabolism of the Glu504 protein is approximately 10-fold higher than that of the Lys504 enzyme. We conclude that the presence of the Lys504 allele contributes in large part to the lack of an efficacious clinical response to nitroglycerin; we recommend that this genetic factor be considered when administering nitroglycerin to patients, especially Asians, 30-50% of whom possess the inactive ALDH2*2 mutant allele.

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“…On the other hand we did not observe any nitric oxide as a hydrolytic degradation product of NG. Nitric oxide has been described as an important degradation product inside mammalian cells and was identified of being responsible in the signaling mechanism in mammalian cells (Di Carlo, 1975;Ignarro et al, 1981;Ignarro, 2002;Kozlov et al, 2003).…”

Section: Intermediates and Products Distributionmentioning

confidence: 99%