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Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation

Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation
Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation

Aims: Heart failure (HF) is a pro-thrombotic state. Both platelet and vascular responses to nitric oxide (NO) donors are impaired in HF patients with reduced ejection fraction (HFrEF) compared to healthy volunteers (HV) due to scavenging of NO, and possibly also reduced activity of the principal NO sensor, soluble guanylate cyclase (sGC), limiting the therapeutic potential of NO donors as anti-aggregatory agents. Previous studies have shown that nitrite inhibits platelet activation presumptively after its reduction to NO, but the mechanism(s) involved remain poorly characterized. Our aim was to compare the effects of nitrite on platelet function in HV vs. HF patients with preserved ejection fraction (HFpEF) and chronic atrial fibrillation (HFpEF-AF), vs. patients with chronic AF without HF, and to assess whether these effects occur independent of the interaction with other formed elements of blood.

Methods and Results: Platelet responses to nitrite and the NO donor sodium nitroprusside (SNP) were compared in age-matched HV controls (n = 12), HFpEF-AF patients (n = 29) and chronic AF patients (n = 8). Anti-aggregatory effects of nitrite in the presence of NO scavengers/sGC inhibitor were determined and vasodilator-stimulated phosphoprotein (VASP) phosphorylation was assessed using Western blotting. In HV and chronic AF, both nitrite and SNP inhibited platelet aggregation in a concentration-dependent manner. Inhibition of platelet aggregation by the NO donor SNP was impaired in HFpEF-AF patients compared to healthy and chronic AF individuals, but there was no impairment of the anti-aggregatory effects of nitrite. Nitrite circumvented platelet NO resistance independently of other blood cells by directly activating sGC and phosphorylating VASP.

Conclusion: We here show for the first time that HFpEF-AF (but not chronic AF without HF) is associated with marked impairment of platelet NO responses due to sGC dysfunction and nitrite circumvents the "platelet NO resistance" phenomenon in human HFpEF, at least partly, by acting as a direct sGC activator independent of NO.

Journal Article
0008-6363
1313–1323
Borgognone, Alessandra
45d13f2e-6153-4924-9b3e-9b7d4fb975b6
Shantsila, Eduard
9132e2d6-b1d9-4125-9ab2-7206c645ee4e
Worrall, Sophie M.
fa8fd5d3-7aa5-41af-9e26-d9f25e5a8de2
Prompunt, Eakkapote
f51b8463-f8a1-4be8-b455-6ebb4fafa660
Loka, Thomas
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Loudon, Brodie L.
b4b8e80a-cc4d-4cea-9b67-a77daa18cfdc
Chimen, Myriam
b6ca7b9a-e08f-482f-8cfb-8c80168aafac
Rainger, G. Ed
f437d109-e403-40a4-895a-21f740503a86
Lord, Janet M.
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Turner, Ashley
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Nightingale, Peter
ee193242-6a0a-4879-a8b4-f936eb92d49b
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Kirchhof, Paulus
7c1bf4e2-8339-48d6-b5bd-2c26efd3ac5f
Lip, Gregory Y H
0bd5d832-d4c4-42c5-8b6f-0289b3277fe5
Watson, Steve P
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Frenneaux, Michael P
82824b6d-51f1-4b31-9f7a-5b4746d59833
Madhani, Melanie
63a48cca-67b7-41ae-bc79-0f4a166f0750
Borgognone, Alessandra
45d13f2e-6153-4924-9b3e-9b7d4fb975b6
Shantsila, Eduard
9132e2d6-b1d9-4125-9ab2-7206c645ee4e
Worrall, Sophie M.
fa8fd5d3-7aa5-41af-9e26-d9f25e5a8de2
Prompunt, Eakkapote
f51b8463-f8a1-4be8-b455-6ebb4fafa660
Loka, Thomas
1a65919e-990d-4e0c-b592-8e5d4be2ac49
Loudon, Brodie L.
b4b8e80a-cc4d-4cea-9b67-a77daa18cfdc
Chimen, Myriam
b6ca7b9a-e08f-482f-8cfb-8c80168aafac
Rainger, G. Ed
f437d109-e403-40a4-895a-21f740503a86
Lord, Janet M.
29f3ed31-5762-4b3f-aca5-3d1049d26830
Turner, Ashley
751444e2-e3ec-48b8-a11c-298d317af567
Nightingale, Peter
ee193242-6a0a-4879-a8b4-f936eb92d49b
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Kirchhof, Paulus
7c1bf4e2-8339-48d6-b5bd-2c26efd3ac5f
Lip, Gregory Y H
0bd5d832-d4c4-42c5-8b6f-0289b3277fe5
Watson, Steve P
5bb8b1bf-5fbe-4d37-be58-16f823141c85
Frenneaux, Michael P
82824b6d-51f1-4b31-9f7a-5b4746d59833
Madhani, Melanie
63a48cca-67b7-41ae-bc79-0f4a166f0750

Borgognone, Alessandra, Shantsila, Eduard, Worrall, Sophie M., Prompunt, Eakkapote, Loka, Thomas, Loudon, Brodie L., Chimen, Myriam, Rainger, G. Ed, Lord, Janet M., Turner, Ashley, Nightingale, Peter, Feelisch, Martin, Kirchhof, Paulus, Lip, Gregory Y H, Watson, Steve P, Frenneaux, Michael P and Madhani, Melanie (2018) Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation. Cardiovascular Research, 114 (10), 1313–1323. (doi:10.1093/cvr/cvy087).

Record type: Article

Abstract

Aims: Heart failure (HF) is a pro-thrombotic state. Both platelet and vascular responses to nitric oxide (NO) donors are impaired in HF patients with reduced ejection fraction (HFrEF) compared to healthy volunteers (HV) due to scavenging of NO, and possibly also reduced activity of the principal NO sensor, soluble guanylate cyclase (sGC), limiting the therapeutic potential of NO donors as anti-aggregatory agents. Previous studies have shown that nitrite inhibits platelet activation presumptively after its reduction to NO, but the mechanism(s) involved remain poorly characterized. Our aim was to compare the effects of nitrite on platelet function in HV vs. HF patients with preserved ejection fraction (HFpEF) and chronic atrial fibrillation (HFpEF-AF), vs. patients with chronic AF without HF, and to assess whether these effects occur independent of the interaction with other formed elements of blood.

Methods and Results: Platelet responses to nitrite and the NO donor sodium nitroprusside (SNP) were compared in age-matched HV controls (n = 12), HFpEF-AF patients (n = 29) and chronic AF patients (n = 8). Anti-aggregatory effects of nitrite in the presence of NO scavengers/sGC inhibitor were determined and vasodilator-stimulated phosphoprotein (VASP) phosphorylation was assessed using Western blotting. In HV and chronic AF, both nitrite and SNP inhibited platelet aggregation in a concentration-dependent manner. Inhibition of platelet aggregation by the NO donor SNP was impaired in HFpEF-AF patients compared to healthy and chronic AF individuals, but there was no impairment of the anti-aggregatory effects of nitrite. Nitrite circumvented platelet NO resistance independently of other blood cells by directly activating sGC and phosphorylating VASP.

Conclusion: We here show for the first time that HFpEF-AF (but not chronic AF without HF) is associated with marked impairment of platelet NO responses due to sGC dysfunction and nitrite circumvents the "platelet NO resistance" phenomenon in human HFpEF, at least partly, by acting as a direct sGC activator independent of NO.

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2018 Borgogne Cardiovasc Res-ahead of print - Version of Record
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Accepted/In Press date: 9 March 2018
e-pub ahead of print date: 12 April 2018
Published date: 1 August 2018
Keywords: Journal Article

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Local EPrints ID: 422584
URI: http://eprints.soton.ac.uk/id/eprint/422584
ISSN: 0008-6363
PURE UUID: 018afcfa-8851-410c-a57b-04476d7f7f94
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 25 Jul 2018 16:30
Last modified: 10 Dec 2019 01:37

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Contributors

Author: Alessandra Borgognone
Author: Eduard Shantsila
Author: Sophie M. Worrall
Author: Eakkapote Prompunt
Author: Thomas Loka
Author: Brodie L. Loudon
Author: Myriam Chimen
Author: G. Ed Rainger
Author: Janet M. Lord
Author: Ashley Turner
Author: Peter Nightingale
Author: Martin Feelisch ORCID iD
Author: Paulus Kirchhof
Author: Gregory Y H Lip
Author: Steve P Watson
Author: Michael P Frenneaux
Author: Melanie Madhani

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