Significance: Liver steatosis, or fatty liver, is the most common liver disease in the world, affecting up to 25% of all Americans. There is currently no approved drug available for this condition, which may progress to serious disease, including steatohepatitis, fibrosis, and cirrhosis. Here, we show in rodent and human models of metabolic syndrome that steatosis can be prevented by a simple dietary approach. Inorganic nitrate, present in green leafy vegetables, is converted in vivo to nitric oxide (NO) in a process involving symbiotic host bacteria. NO then induces key metabolic regulatory pathways to ultimately reduce oxidative stress and improve cardiometabolic functions. Clinical trials would be helpful to tell if dietary nitrate is useful in treatment and prevention of fatty liver disease.

Cardiovascular disorders including hypertension and associated renal disease are major health problems affecting more than 1.5 billion people worldwide. Apart from nonmodifiable factors such as ageing, family history and gender, both sedentary lifestyle and unhealthy dietary habits are considered as major risk factors. The disorders are interrelated suggesting common pathological pathways. Mechanistically, oxidative stress and compromised function of the nitric oxide synthase (NOS) system leading to endothelial dysfunction and reduction in nitric oxide (NO) bioavailability have been widely implicated and associated with development and progression of disease. New strategies that correct this redox imbalance and increase NO bioactivity may have major clinical implications. The inorganic anions, nitrate and nitrite, are endogenously formed by oxidization of NOS‐derived NO, but there are also high amounts of nitrate in our daily diet. In this regard, accumulated evidence over the past two decades demonstrates that these anions can be recycled back to NO and other bioactive nitrogen oxides, thus offering an attractive alternative strategy for therapeutic exploitation. In this review, we describe how dietary stimulation of the nitrate–nitrite–NO pathway affects cardiovascular and renal functions in health and disease via modulation of oxidative stress and NO bioavailability. Clinical studies addressing potential effects on the renal system are still limited, but blood pressure‐lowering effects of nitrate supplementation have been demonstrated in healthy and hypertensive subjects as well as in patients with chronic kidney disease. However, larger clinical studies are warranted to reveal whether chronic nitrate treatment can slow‐down the progression of cardiorenal disease and associated complications.

Background and purpose: Increased oxidative stress and up‐regulation of matrix metalloproteinases (MMPs) may cause structural and functional vascular changes in renovascular hypertension. We examined whether treatment with spironolactone (SPRL), hydrochlorothiazide (HCTZ) or both drugs together modified hypertension‐induced changes in arterial blood pressure, aortic remodelling, vascular reactivity, oxidative stress and MMP levels and activity, in a model of renovascular hypertension.Experimental approach: We used the two‐kidney,one‐clip (2K1C) model of hypertension in Wistar rats. Sham‐operated or hypertensive rats were treated with vehicle, SPRL (25 mg·kg⁻¹·day⁻¹), HCTZ (20 mg·kg⁻¹·day⁻¹) or a combination for 8 weeks. Systolic blood pressure was monitored weekly. Aortic rings were isolated to assess endothelium‐dependent and ‐independent relaxations. Morphometry of the vascular wall was carried out in sections of aorta. Aortic NADPH oxidase activity and superoxide production were evaluated. Formation of reactive oxygen species was measured in plasma as thiobarbituric acid‐reactive substances. Aortic MMP‐2 levels and activity were determined by gelatin andin situzymography, fluorimetry and immunohistochemistry.Key results: Treatment with SPRL, HCTZ or the combination attenuated 2K1C‐induced hypertension, and reversed the endothelial dysfunction in 2K1C rats. Both drugs or the combination reversed vascular aortic remodelling induced by hypertension, attenuated hypertension‐induced increases in oxidative stress and reduced MMP‐2 levels and activity.Conclusions and implications: SPRL or HCTZ, alone or combined, exerted antioxidant effects, and decreased renovascular hypertension‐induced MMP‐2 up‐regulation, thus improving the vascular dysfunction and remodelling found in this model of hypertension.

Rationale: Recovering the neutrophil migration to the infectious focus improves survival in severe sepsis. Recently, we demonstrated that the cystathionine γ-lyase (CSE)/hydrogen sulfide (H₂S) pathway increased neutrophil recruitment to inflammatory focus during sterile inflammation. Objectives: To evaluate if H₂S administration increases neutrophil migration to infectious focus and survival of mice. Methods: Sepsis was induced by cecal ligation and puncture (CLP). Measurements and Main Results: The pretreatments of mice with H₂S donors (NaHS or Lawesson's reagent) improved leukocyte rolling/adhesion in the mesenteric microcirculation as well as neutrophil migration. Consequently, bacteremia levels were reduced, hypotension and lung lesions were prevented, and the survival rate increased from approximately 13% to approximately 80%. Even when treatment was delayed (6 h after CLP), a highly significant reduction in mortality compared with untreated mice was observed. Moreover, H₂S pretreatment prevented the down-regulation of CXCR2 and l-selectin and the up-regulation of CD11b and G protein–coupled receptor kinase 2 in neutrophils during sepsis. H₂S also prevented the reduction of intercellular adhesion molecule–1 expression in the endothelium of the mesenteric microcirculation in severe sepsis. Confirming the critical role of H₂S on sepsis outcome, pretreatment with dl-propargylglycine (a CSE inhibitor) inhibited neutrophil migration to the infectious focus, enhanced lung lesions, and induced high mortality in mice subjected to nonsevere sepsis (from 0 to ∼80%). The beneficial effects of H₂S were blocked by glibenclamide (a ATP-dependent K⁺ channel blocker). Conclusions: These results showed that H₂S restores neutrophil migration to the infectious focus and improves survival outcome in severe sepsis by an ATP-dependent K⁺ channel–dependent mechanism.