Nitrite Regulates Hypoxic Vasodilation via Myoglobin-Dependent Nitric Oxide Generation

Totzeck, Matthias; Hendgen‐Cotta, Ulrike B.; Luedike, Peter; Berenbrink, Michael; Klare, Johann P.; Steinhoff, Heinz‐Jürgen; Semmler, Dominik; Shiva, Sruti; Williams, Daryl R.; Kipar, Anja; Gladwin, Mark T.; Schrader, Juergen; Kelm, Malte; Cossins, Andrew R.; Rassaf, Tienush

doi:10.1161/circulationaha.111.087155

Cited by 177 publications

(161 citation statements)

References 48 publications

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“…In particular, Mb is the main regulator of the vasodilatory response in muscles (27) and Hb appears to be the main protein regulating NO production from nitrite in the human RBCs (11). As platelet activation is inhibited by NO, platelet activation assays are useful and biologically relevant models to assess the release of NO from nitrite reactions with globins and intact RBCs.…”

Section: Resultsmentioning

confidence: 99%

Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells

Cortí

Xue

Tejero

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The discovery of novel globins in diverse organisms has stimulated intense interest in their evolved function, beyond oxygen binding. Globin X (GbX) is a protein found in fish, amphibians, and reptiles that diverged from a common ancestor of mammalian hemoglobins and myoglobins. Like mammalian neuroglobin, GbX was first designated as a neuronal globin in fish and exhibits six-coordinate heme geometry, suggesting a role in intracellular electron transfer reactions rather than oxygen binding. Here, we report that GbX to our knowledge is the first six-coordinate globin and the first globin protein apart from hemoglobin, found in vertebrate RBCs. GbX is present in fish erythrocytes and exhibits a nitrite reduction rate up to 200-fold faster than human hemoglobin and up to 50-fold higher than neuroglobin or cytoglobin. Deoxygenated GbX reduces nitrite to form nitric oxide (NO) and potently inhibits platelet activation in vitro, to a greater extent than hemoglobin. Fish RBCs also reduce nitrite to NO and inhibit platelet activation to a greater extent than human RBCs, whereas GbX knockdown inhibits this nitrite-dependent NO signaling. The description of a novel, sixcoordinate globin in RBCs with dominant electron transfer and nitrite reduction functionality provides new insights into the evolved signaling properties of ancestral heme-globins.nitrite | nitric oxide | blood | RBC | platelet

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Section: Resultsmentioning

confidence: 99%

Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells

Cortí

Xue

Tejero

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Nitrite anion acts as a NO reservoir that can be readily converted to NO by a non-enzymatic one electron reduction by deoxyhemoglobin, deoxymyoglobin, xanthine oxidoreductase and other mechanisms, making it a unique candidate for potential therapeutic effect in ischemic tissues. 22,23 In this way, nitrite reduction to NO preferentially occurs during tissue hypoxia where O 2 concentrations for NOS function (O 2 K m = 24 µM) may be compromised. Thus, nitrite therapy could be a useful alternative source of bioavailable NO to alleviate endothelial cell dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Sodium nitrite in patients with peripheral artery disease and diabetes mellitus: Safety, walking distance and endothelial function

et al. 2013

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Nitrite stores decrease after exercise in patients with peripheral artery disease (PAD) and diabetes represents decreased nitric oxide (NO) bioavailability that may contribute to endothelial dysfunction and limit exercise duration. The primary objective of this placebo-controlled study was the safety and tolerability of multiple doses of oral sodium nitrite in patients with PAD, predominantly with diabetes, over a period of 10 weeks. The primary efficacy endpoint was endothelial flow-mediated dilatation (FMD) and secondary efficacy endpoints included a 6-minute walk test and quality of life assessment. Of the 55 subjects, the most common side effects attributed to sodium nitrite were a composite of headache and dizziness occurring in 21% with the 40 mg dose and 44% with the 80 mg dose. There was no clinically significant elevation of methemoglobin. FMD non-significantly worsened in the placebo and 40 mg groups, but was stable in the 80 mg group. Diabetic patients receiving 80 mg had significantly higher FMD compared with the placebo and 40 mg groups. There was no significant change in 6-minute walk test or quality of life parameters over time compared to placebo. In conclusion, sodium nitrite therapy is well tolerated in patients with PAD. The possible clinical benefit of sodium nitrite should be studied in a larger and fully powered trial.

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“…However, the biochemistry has been difficult to resolve (176). Myoglobin (Mb) heme appears to be key to hypoxic vasodilation, as it is present in rat aortic smooth muscle and in Mb null rats (Mb -y-) hypoxic vasodilation is impaired (170). Recently, Miljkovic et al (106) showed that H 2 S is a rapid mediator of nitrite reduction by providing reducing equivalents to Fe 3 + , thereby generating both NO and its reduced congener, nitroxyl (HNO).…”

Section: Reactions With No and Related Compoundsmentioning

confidence: 99%

Hydrogen sulfide as an oxygen sensor

Olson

2013

Clinical Chemistry and Laboratory Medicine

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Significance: Although oxygen (O 2 )-sensing cells and tissues have been known for decades, the identity of the O 2 -sensing mechanism has remained elusive. Evidence is accumulating that O 2 -dependent metabolism of hydrogen sulfide (H 2 S) is this enigmatic O 2 sensor. Recent Advances: The elucidation of biochemical pathways involved in H 2 S synthesis and metabolism have shown that reciprocal H 2 S/O 2 interactions have been inexorably linked throughout eukaryotic evolution; there are multiple foci by which O 2 controls H 2 S inactivation, and the effects of H 2 S on downstream signaling events are consistent with those activated by hypoxia. H 2 S-mediated O 2 sensing has been demonstrated in a variety of O 2 -sensing tissues in vertebrate cardiovascular and respiratory systems, including smooth muscle in systemic and respiratory blood vessels and airways, carotid body, adrenal medulla, and other peripheral as well as central chemoreceptors. Critical Issues: Information is now needed on the intracellular location and stoichometry of these signaling processes and how and which downstream effectors are activated by H 2 S and its metabolites. Future Directions: Development of specific inhibitors of H 2 S metabolism and effector activation as well as cellular organelle-targeted compounds that release H 2 S in a timeor environmentally controlled way will not only enhance our understanding of this signaling process but also provide direction for future therapeutic applications. Antioxid. Redox Signal. 22, 377-397.

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Nitrite Regulates Hypoxic Vasodilation via Myoglobin-Dependent Nitric Oxide Generation

Cited by 177 publications

References 48 publications

Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells

Globin X is a six-coordinate globin that reduces nitrite to nitric oxide in fish red blood cells

Sodium nitrite in patients with peripheral artery disease and diabetes mellitus: Safety, walking distance and endothelial function

Hydrogen sulfide as an oxygen sensor

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