| 1. |
- Carlström, Mattias, et al.
(author)
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Cross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis
- 2015
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In: Antioxidants and Redox Signaling. - : Mary Ann Liebert Inc. - 1523-0864 .- 1557-7716. ; 23:4, s. 295-306
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Journal article (peer-reviewed)abstract
- Aims: Inorganic nitrate and nitrite from endogenous and dietary sources have emerged as alternative substrates for nitric oxide (NO) formation in addition to the classic L-arginine NO synthase (NOS)-dependent pathway. Here, we investigated a potential cross-talk between these two pathways in the regulation of vascular function. Results: Long-term dietary supplementation with sodium nitrate (0.1 and 1mmol kg(-1) day(-1)) in rats caused a reversible dose-dependent reduction in phosphorylated endothelial NOS (eNOS) (Ser1177) in aorta and a concomitant increase in phosphorylation at Thr495. Moreover, eNOS-dependent vascular responses were attenuated in vessels harvested from nitrate-treated mice or when nitrite was acutely added to control vessels. The citrulline-to-arginine ratio in plasma, as a measure of eNOS activity, was reduced in nitrate-treated rodents. Telemetry measurements revealed that a low dietary nitrate dose reduced blood pressure, whereas a higher dose was associated with a paradoxical elevation. Finally, plasma cyclic guanosine monophosphate increased in mice that were treated with a low dietary nitrate dose and decreased with a higher dose. Innovation and Conclusions: These results demonstrate the existence of a cross-talk between the nitrate-nitrite-NO pathway and the NOS-dependent pathway in control of vascular NO homeostasis. Antioxid. Redox Signal. 23, 295-306.
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| 3. |
- Huang, Liyue
(author)
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Nitric oxide formation from inorganic nitrate and nitrate : contribution from eukaryotic and prokaryotic pathways
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Nitric oxide (NO) is an essential signaling molecule that plays a central role in a broad range of physiological functions. Classically, NO is synthesized from L-arginine and molecular oxygen by NO synthases. Once formed, it is rapidly oxidized to nitrite and nitrate. These two inorganic anions were previously considered to be inert end products but this view is now being seriously challenged by research revealing that nitrite can be physiological reduced to again generate NO. The reduction of nitrite in vivo seems particularly enhanced during hypoxia and acidosis; conditions when the oxygen-dependent NO-synthase pathway is dysfunctional. Besides the endogenous formation of nitrate and nitrite by NO synthase, these anions are also ingested naturally via the diet. The first step in bioactivation of nitrate is formation of the more reactive nitrite anion; a reaction suggested to involve oral nitrate reducing bacteria. It has been generally viewed that mammalian cells cannot metabolize the stable nitrate anion. In the present thesis, we intended to further characterize NO generation from the nitrate-nitrite-NO pathway. In particular we have studied the importance of commensal bacteria in nitrate metabolism and attempted to explore if mammalian tissues are also capable of nitrate reduction. We also studied possible interactions between the classical NO synthase pathway and the nitrate-nitrite-NO pathway. We show that bacteria in the gastrointestinal tract play an interesting role in mammalian NO biology. Besides the bioactivation of nitrate in the oral cavity to form nitrite, bacteria in the small and large intestine can catalyze the same reaction and also the subsequent reduction of nitrite to form NO. NO formation in the gut can be stimulated in vivo by supplementation with dietary nitrate and probiotic bacteria. In further studies involving also germ-free mice, we surprisingly find that inorganic nitrate is enzymatically reduced to nitrite in tissues and we identify the enzyme xanthine oxidoreductase (XOR) as the dominant nitrate reductase. Mammalian nitrate reductase activity is enhanced during hypoxic conditions but is also active during normoxia. The functional consequences of this nitrate reductase activity were studied after nitrate administration in vivo. Nitrate attenuated the increased blood pressure caused by an NO synthase inhibitor and prevented the severe decline in blood flow during post-ischemic reperfusion. The expression of XOR is enhanced in tissues of germ free mice, which may reflect a feedback response to the absence of bacterial nitrate reduction in these animals. Such crosstalk is further supported in a study of long-term dietary nitrate supplementation in rats, in which expression of phosphorylated eNOS in aortic tissue and eNOS activity was down-regulated after nitrate supplementation. All together these data suggest a crosstalk between NOS-independent and NOS-dependent pathways in control of NO vascular homeostasis. In summary, the present thesis helps to draw a new picture of mammalian NO generation which occurs by serial reductions of the supposedly inert anions nitrate and nitrite. In this pathway both eukaryotic and prokaryotic pathways contribute to formation of NO and maintenance of homeostasis. Intriguingly, NO formation from nitrate in the gastrointestinal tract, the cardiovascular system and elsewhere, can be controlled by simple dietary interventions with resulting physiological effects.
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| 4. |
- Jansson, Emmelie Å, et al.
(author)
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A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis
- 2008
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In: Nature Chemical Biology. - : Springer Science and Business Media LLC. - 1552-4450 .- 1552-4469. ; 4:7, s. 411-417
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Journal article (peer-reviewed)abstract
- Inorganic nitrite (NO(2)(-)) is emerging as a regulator of physiological functions and tissue responses to ischemia, whereas the more stable nitrate anion (NO(3)(-)) is generally considered to be biologically inert. Bacteria express nitrate reductases that produce nitrite, but mammals lack these specific enzymes. Here we report on nitrate reductase activity in rodent and human tissues that results in formation of nitrite and nitric oxide (NO) and is attenuated by the xanthine oxidoreductase inhibitor allopurinol. Nitrate administration to normoxic rats resulted in elevated levels of circulating nitrite that were again attenuated by allopurinol. Similar effects of nitrate were seen in endothelial NO synthase-deficient and germ-free mice, thereby excluding vascular NO synthase activation and bacteria as the source of nitrite. Nitrate pretreatment attenuated the increase in systemic blood pressure caused by NO synthase inhibition and enhanced blood flow during post-ischemic reperfusion. Our findings suggest a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis.
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