Accelerating inflammatory resolution in humans to improve endothelial function and vascular health: Targeting the non-canonical pathway for NO

IF 10.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology Pub Date : 2025-03-28 DOI:10.1016/j.redox.2025.103592

Clement Lau , Christopher P. Primus , Asad Shabbir , Ismita Chhetri , Mutsumi Ono , Michael Masucci , Muhammad Aadil Bin Noorany Aubdool , Julie Amarin , Alexander JP. Hamers , Zara Khan , Nitin Ajit Kumar , Shanik A. Montalvo Moreira , Gani Nuredini , Miski Osman , Charlotte Whitear , Tom Godec , Vikas Kapil , Gianmichele Massimo , Rayomand S. Khambata , Krishnaraj S. Rathod , Amrita Ahluwalia

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引用次数: 0

Abstract

Background

Chronic cardiovascular diseases (CVD) are characterised by low-grade systemic inflammation in part due to reduced nitric oxide (NO) bioavailability associated with endothelial dysfunction. Bioavailability of NO can be enhanced by activation of the non-canonical pathway, through increased dietary inorganic nitrate consumption with the potential to attenuate inflammation.

Methods

We sought to determine whether dietary inorganic nitrate influences the inflammatory response in models of localised (cantharidin-induced blisters) and systemic inflammation (typhoid vaccine), in healthy male volunteers and conducted two clinical trials; Blister-NITRATE and Typhoid-NITRATE respectively.

Results

We show that dietary nitrate attenuates endothelial dysfunction following typhoid vaccine administration and accelerates resolution of cantharidin-induced blisters. Both phenomena were associated with an increased level of pro-resolving mediators consequent to a reduction in the expression and activity of pro-inflammatory monocytes. Moreover, we show that leukocytes of the monocyte lineage express the nitrite reductase XOR, that may drive localised nitrite reduction to elevate NO (and cGMP) to drive the protective phenotype.

Conclusions

Inorganic nitrate improves endothelial function in the setting of systemic inflammation. Whilst the immediate inflammatory response appeared unaffected by inorganic nitrate treatment, during the resolution phase of the acute inflammatory response lower levels of pro-inflammatory classical inflammatory and intermediate monocytes and attenuated levels of inflammatory cytokines and chemokines were evident. We propose that this reflects a pro-resolution phenotype that may be of potential therapeutic benefit in patients with established CVD.

Clinical trial registration

URL: https://www.clinicaltrials.gov; unique identifiers NCT02715635, NCT03183830.

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来源期刊

Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-

CiteScore

19.90

自引率

3.50%

发文量

318

审稿时长

25 days

期刊介绍： Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.