Redox state, oxidative stress and endothelial dysfunction in heart failure: the puzzle of nitrate-thiol interaction.
Endothelial dysfunction, a critical component in the progression of heart failure, may result from increased oxidative stress, secondary to activation of the adrenergic and the renin-angiotensin systems and to the production of inflammatory cytokines, which in turn contribute to reduced bioavailability of nitric oxide (NO). Oxidative stress, determined by excess production of reactive oxygen species and impairment in the antioxidant defence, is responsible for both the decline of diffusible NO and the decrease in the concentration of essential co-factors of NO synthases. Reactive oxygen species are formed from NO in the presence of oxidants and are involved in the nitration of protein tyrosine residue that can alter protein function. Recent studies re-addressed the impact of nitrate treatment in heart failure in view of the beneficial vascular and cellular effects of NO, and of the discovery of abnormalities in NO pathways in this disease. Concerns exist, however, on the safety of nitrates in this setting. Nitrates stimulate vascular superoxide anion production via activation of NADPH oxidase, and induction of uncoupling of NO synthase. Furthermore, by using donors of sulfhydryl groups, such as cysteine and glutathione, for NO production, nitrates may favour depletion of the intracellular thiol pool, thus impairing the antioxidant defence mechanisms.
Parodi
Oberdan
O
CNR Clinical Physiology Institute of Milan, Cardiology Department, Niguarda Ca' Granda Hospital, Milan, Italy. ifcnig@tin.it
De Maria
Renata
R
Roubina
Elena
E
D004730:Endothelium, Vascular / Q000503:physiopathology*; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D009566:Nitrates / Q000502:physiology*; D009569:Nitric Oxide; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D013438:Sulfhydryl Compounds / Q000502:physiology*
D009566:Nitrates; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide