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

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 proinflammatory 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.