Resistance artery vasodilation in response to hypoxia is essential for matching tissue oxygen and demand. In hypoxia, erythrocytic hemoglobin tetramers produce nitric oxide through nitrite reduction. We hypothesized that the alpha subunit of hemoglobin expressed in endothelium also facilitates nitrite reduction proximal to smooth muscle. Here, we create two mouse strains to test this: an endothelial-specific alpha globin knockout (EC Hba1Δ/Δ) and another with an alpha globin allele mutated to prevent alpha globin’s inhibitory interaction with endothelial nitric oxide synthase (Hba1WT/Δ36–39). The EC Hba1Δ/Δ mice had significantly decreased exercise capacity and intracellular nitrite consumption in hypoxic conditions, an effect absent in Hba1WT/Δ36–39 mice. Hypoxia-induced vasodilation is significantly decreased in arteries from EC Hba1Δ/Δ, but not Hba1WT/Δ36–39 mice. Hypoxia also does not lower blood pressure in EC Hba1Δ/Δ mice. We conclude the presence of alpha globin in resistance artery endothelium acts as a nitrite reductase providing local nitric oxide in response to hypoxia.

Objective: This single-center clinical study identifies clusters of different phenotypes and pathophysiology subtypes of patients with gout and associated comorbidities.Methods: Patients clinically diagnosed with gout were enrolled between January 2018 and December 2019. Hierarchical cluster analyses were performed using clinical data or biological markers, inflammatory markers, and oxidative stress pathway metabolites assayed from serum and plasma samples. Subgroup clusters were compared using ANOVA for continuous data and chi-square tests for categorical data.Results: Hierarchical cluster analysis identified 3 clusters. Cluster 1 (C1; n = 24) comprised dyslipidemia, hypertension, and early-onset gout, without tophi. Cluster 2 (C2; n = 25) comprised hypertension, dyslipidemia, nephrolithiasis, and obesity. Cluster 3 (C3; n = 39) comprised multiple comorbidities and tophi. Post hoc comparisons of data obtained from samples of patients in C1, C2, and C3 revealed significant differences in the levels of oxidative stress and inflammation-related markers, including 3-nitrotyrosine, tumor necrosis factor, C-reactive protein, interleukin (IL) 1β, IL-6, platelet-derived growth factor (PDGF)–AA, and PDGF-BB. Reclustering patients based on all markers as well as on the biological markers that significantly differed among the initial clusters identified similar clusters.Conclusion: Oxidative stress and inflammatory marker levels may affect the development and clinical manifestations (ie, clinical phenotypes) of gout. Measuring oxidative stress and levels of inflammatory cytokines is a potential adjunctive tool and biomarker for early identification and management of gout.

Physical inactivity and poor dietary choices contribute to the rise in cardiometabolic diseases in the United States. It remains critical to identify strategies that may mitigate the negative impact of these behaviors. Several studies have shown that the consumption of dietary inorganic nitrate may improve vascular health and glucose regulation in animal models and some human studies. However, the improvements in glucose regulation have yet to be corroborated in humans with type 2 diabetes (T2D). Therefore, the purpose of this study was to assess the acute effects of beetroot juice (BRJ) on glycemic and hemodynamic responses in individuals with T2D while controlling for medication. Seven participants with a clinical diagnosis of T2D were recruited into this study and were temporarily removed from blood pressure- and glucose-lowering medications. Hemodynamic measurements (pulsewave velocity) and an oral glucose tolerance test (glycemic response) were measured following consumption of either BRJ or a denitrolized placebo. Saliva and blood samples were collected at baseline and two and four hours post supplementation to measure changes in nitrate and nitrite concentrations. We detected significant improvements in total plasma glucose exposure (p = 0.022) and the SVR change score (p = 0.009) in the BRJ condition. This study demonstrated that BRJ consumption can improve oral glucose tolerance in individuals with T2D while controlling for medication; however, future larger-cohort randomized controlled trials are needed to confirm if BRJ is a viable treatment for glucose control in individuals with T2D.

Background/Objectives: Hemolysis has been associated with acute kidney injury (AKI) in infants and neonates after surgery involving cardiopulmonary bypass (CPB). Erythrocyte hemolysis and subsequent end-organ injury have been shown to be a complex process involving the liberation of multiple molecules that mediate the loss of nitric oxide and oxidative damage. This study assesses the association of multiple products of erythrocyte hemolysis with the evolution of AKI in neonates and infants undergoing CPB surgery. Methods: Blood and urine samples were collected at multiple time points before and after CPB and stored within an institutional biorepository. Twenty-one patients with AKI were matched with twenty-one non-Aki patients based on demographic and case complexity data. Results: Samples were analyzed for cell-free hemoglobin, heme, non-transferrin-bound iron, haptoglobin, hemopexin, and nitrite/nitrate. NGAL and KIM-1 were measured to index AKI. Cell-free hemoglobin was higher, haptoglobin was lower, and haptoglobin:hemoglobin ratio was lower in AKI compared to non-AKI patients. Conclusions: AKI in neonates and infants after CPB is associated with a pre and postoperative decrease in serum haptoglobin. These results confirm the need for future studies to prevent injury from hemolysis during CPB and potentially identify at-risk patients with decreased haptoglobin levels before surgery if delay is an option.