Endothelial nitric oxide synthase in red blood cells: key to a new erythrocrine function? - PubMed (original) (raw)

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Endothelial nitric oxide synthase in red blood cells: key to a new erythrocrine function?

Miriam M Cortese-Krott et al. Redox Biol. 2014.

Abstract

Red blood cells (RBC) have been considered almost exclusively as a transporter of metabolic gases and nutrients for the tissues. It is an accepted dogma that RBCs take up and inactivate endothelium-derived NO via rapid reaction with oxyhemoglobin to form methemoglobin and nitrate, thereby limiting NO available for vasodilatation. Yet it has also been shown that RBCs not only act as "NO sinks", but exert an erythrocrine function - i.e an endocrine function of RBC - by synthesizing, transporting and releasing NO metabolic products and ATP, thereby potentially controlling systemic NO bioavailability and vascular tone. Recent work from our and others laboratory demonstrated that human RBCs carry an active type 3, endothelial NO synthase (eNOS), constitutively producing NO under normoxic conditions, the activity of which is compromised in patients with coronary artery disease. In this review we aim to discuss the potential role of red cell eNOS in RBC signaling and function, and to critically revise evidence to this date showing a role of non-endothelial circulating eNOS in cardiovascular pathophysiology.

Keywords: Cardiovascular disease; Nitric oxide; Red blood cells; eNOS.

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Graphical abstract

Fig. 1

Fig. 1

Upper panel: The expression of eNOS in the endothelium of the vessels decreases along the vascular tree, while blood cell eNOS carried by all main blood populations is equally distributed. Middle panel: In the blood compartment a circulating pool of NO metabolites is formed and transported in plasma and RBC. Bottom panel: NO can be synthesized enzymatically from L-arginine under normoxic conditions in a reaction catalyzed by a NOS, and under hypoxic conditions from nitrite by the nitrate reductase activity of proteins including deoxyhemoglobin (deoxyHb), deoxymyoglobin (deoxyMb), xantine oxidoreductase (XOR), carbonic anydrase (CA), and cytochrome C (cytC)/cytC-oxidase. eNOS, endothelial nitric oxide synthase; LNO2, nitrated lipids; RSNO, nitrosothiols; RNNO, nitrosamines.

Fig. 2

Fig. 2

Potential role of red cell eNOS in signalling. L-arginine is imported into the RBC via the cationic amino acid transporters y+/CAT and/or y+L. Both localization of eNOS on the cytoplasmic side of the RBC membrane and protein-protein interactions may play a central role in effectively separating eNOS from arginase, as well as NO production from NO scavenging by oxyhemoglobin (oxyHb). Local formation of methemoglobin (metHb) by reaction of eNOS-derived NO may protect further produced NO from degradation by oxyHb, allowing NO to interact with target proteins in the immediate vicinity of eNOS to exert intracellular signaling function, leading to activation of NO signaling pathways. An example of such a target might be the Pannexin-1 channel.

Fig. 3

Fig. 3

Creation in vivo chimera models for studying the role of blood cell eNOS. To analyze the role of blood cell eNOS we created chimeras carrying eNOS in the blood only (group II) or lacking eNOS in the blood only (group III) and respective controls (groups I, IV) by cross-transplanting the bone marrow of wild type (WT) or eNOS knockout (eNOS-/-) mice into lethal irradiated mice. We found that also blood cell eNOS play a role in control of vascular tone and cardioprotection.

Fig. 4

Fig. 4

Pathophysiological significance of red cell eNOS. An accumulating body of evidence identifies RBCs as active contributors to vascular homeostasis and cardioprotection. These effects might be due to the ability of RBCs to secrete vasoactive and cardioprotective molecules, a property which we here define as erythrocrine function, and might be dependent on the activity of red cell eNOS. Further studies are required to unravel its nature, regulation and pathophysiological significance.

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References

    1. Moncada S., Palmer R.M.J., Higgs E.A. Nitric oxide, biology pathophysiology and pharmacology. Pharmacol. Rev. 1991;43:109–142. - PubMed
    1. Furchgott R.F., Zawadzki J.V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–376. - PubMed
    1. Ignarro L.J. Biological actions and properties of endothelium-derived nitric oxide formed and released from artery and vein. Circ. Res. 1989;65:1–21. - PubMed
    1. Palmer R.M., Ferrige A.G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–526. - PubMed
    1. Vallance P., Collier J., Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet. 1989;2:997–1000. - PubMed

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