Nitrosothiols in the immune system: Signaling and protection

Antioxidants and Redox Signaling 18.3 (2013): 288-308Significance: In the immune system, nitric oxide (NO) has been mainly associated with antibacterial defenses exerted through oxidative, nitrosative, and nitrative stress and signal transduction through cyclic GMP-dependent mechanisms. However, S-nitrosylation is emerging as a post-translational modification (PTM) involved in NO-mediated cell signaling. Recent Advances: Precise roles for S-nitrosylation in signaling pathways have been described both for innate and adaptive immunity. Denitrosylation may protect macrophages from their own S-nitrosylation, while maintaining nitrosative stress compartmentalized in the phagosomes. Nitrosothiols have also been shown to be beneficial in experimental models of autoimmune diseases, mainly through their role in modulating T-cell differentiation and function. Critical Issues: Relationship between S-nitrosylation, other thiol redox PTMs, and other NO-signaling pathways has not been always taken into account, particularly in the context of immune responses. Methods for assaying S-nitrosylation in individual proteins and proteomic approaches to study the S-nitrosoproteome are constantly being improved, which helps to move this field forward. Future Directions: Integrated studies of signaling pathways in the immune system should consider whether S-nitrosylation/denitrosylation processes are among the PTMs influencing the activity of key signaling and adaptor proteins. Studies in pathophysiological scenarios will also be of interest to put these mechanisms into broader contexts. Interventions modulating nitrosothiol levels in autoimmune disease could be investigated with a view to developing new therapiesFinanced by the Spanish Government grants CSD2007-00020 (RosasNet, Consolider-Ingenio 2010 programme), CP07/00143 (Miguel Servet programme), and PS09/00101; and PI10/0213

Polymorphism in NEDD4L Is Associated with Increased Salt Sensitivity, Reduced Levels of P-renin and Increased Levels of Nt-proANP

OBJECTIVE: Neuronal precursor cell expressed developmentally down-regulated 4-like (NEDD4L) is a regulator of the amiloride-sensitive epithelial sodium channel (ENaC), thus a candidate gene for salt sensitivity. Carriers of an intact NEDD4L C2-domain, encoded by the NEDD4L rs4149601 (G/A) GG genotype, together with the C-allele of the NEDD4L rs2288774 (C/T) polymorphism have previously been shown to have increased blood pressure. Our aim was to test if genetic variation in NEDD4L is associated with increased salt sensitivity. METHODS: 39 normotensive subjects were studied. The difference in 24-hour systolic blood pressure after four weeks on 150 mmol/day NaCl intake and four weeks on 50 mmol/day NaCl was defined as salt sensitivity. The rs4149601 and rs2288774 polymorphisms were genotyped using PCR-based techniques. RESULTS: Carriers of the rs4149601 GG-genotype together with the rs2288774 CC-genotype had significantly higher salt sensitivity (median, IQR) (18.0, 7.5–20.0 mmHg vs 6.0, 0.0–10.0 mmHg, P = 0.007) and lower plasma renin concentration (P-renin) (6.0, 2.0–9.5 mU/L vs 15.0, 9.0–24.0 mU/L, P = 0.005) as compared to non-carriers of these genotypes. In carriers of the rs4149601 GG-genotype together with the rs2288774 CC- or CT-genotype, as compared to non-carriers, salt sensitivity was (8.0, 6.0–18.0 mmHg vs 5.0, 0.0–10.0 mmHg, P = 0.07) and P-renin (9.0, 6.0–16.0 mU/L vs 15.0, 9.0–28.0 mU/L, P = 0.03). CONCLUSION: Genetic NEDD4L variation seems to affect salt sensitivity and P-renin in normotensive subjects, suggesting that genotyping of NEDD4L may be clinically useful in order to identify subjects who benefit from dietary salt restriction in the prevention of hypertension

Risk of high blood pressure in salt workers working near salt milling plants: A cross-sectional and interventional study

BACKGROUND: Workers working close to salt milling plants may inhale salt particles floating in the air, leading to a rise in plasma sodium, which, in turn, may increase the blood pressure and the risk of hypertension. METHODS: To test the above hypothesis, occupational health check-up camps were organized near salt manufacturing units and all workers were invited for a free health examination. The workers who worked with dry salt in the vicinity of salt milling plants were defined as "non-brine workers," while those working in brine pans located far away from milling plants were defined as "brine workers." Blood pressure (BP) was measured during each clinical examination. In all, 474 non-brine workers and 284 brine workers were studied. RESULTS: Mean systolic blood pressure of non-brine workers (122.1 ± 13.3 mm Hg) was significantly higher than that of brine workers (118.8 ± 12.8 mm Hg, p < 0.01). Mean diastolic blood pressure of non-brine workers (71.5 ± 10.4 mm Hg) was significantly higher than that of brine workers (69.7 ± 9.4 mm Hg, p = 0.02). The prevalence of hypertension was significantly higher in non-brine workers (12.2%) than in brine workers (7.0%, p = 0.02). Nineteen salt workers were monitored while they used face masks and spectacles, for six days. Systolic, as well as diastolic, blood pressure of these workers began declining on the third day and continued to decline on the fourth day, but remained stationary up to the sixth day. The concentration of salt particles in the breathing zone of these workers was 376 mg/m(3 )air. CONCLUSION: Inhalation of salt particles in non-brine workers may be an occupational cause of increased blood pressure

Feasibility and antihypertensive effect of replacing regular salt with mineral salt -rich in magnesium and potassium- in subjects with mildly elevated blood pressure

<p>Abstract</p> <p>Background</p> <p>High salt intake is linked to hypertension whereas a restriction of dietary salt lowers blood pressure (BP). Substituting potassium and/or magnesium salts for sodium chloride (NaCl) may enhance the feasibility of salt restriction and lower blood pressure beyond the sodium reduction alone. The aim of this study was to determine the feasibility and effect on blood pressure of replacing NaCl (Regular salt) with a novel mineral salt [50% sodium chloride and rich in potassium chloride (25%), magnesium ammonium potassium chloride, hydrate (25%)] (Smart Salt).</p> <p>Methods</p> <p>A randomized, double-blind, placebo-controlled study was conducted with an intervention period of 8-weeks in subjects (n = 45) with systolic (S)BP 130-159 mmHg and/or diastolic (D)BP 85-99 mmHg. During the intervention period, subjects consumed processed foods salted with either NaCl or Smart Salt. The primary endpoint was the change in SBP. Secondary endpoints were changes in DBP, daily urine excretion of sodium (24-h dU-Na), potassium (dU-K) and magnesium (dU-Mg).</p> <p>Results</p> <p>24-h dU-Na decreased significantly in the Smart Salt group (-29.8 mmol; p = 0.012) and remained unchanged in the control group: resulting in a 3.3 g difference in NaCl intake between the groups. Replacement of NaCl with Smart Salt resulted in a significant reduction in SBP over 8 weeks (-7.5 mmHg; p = 0.016). SBP increased (+3.8 mmHg, p = 0.072) slightly in the Regular salt group. The difference in the change of SBP between study groups was significant (p < 0.002).</p> <p>Conclusions</p> <p>The substitution of Smart Salt for Regular salt in subjects with high normal or mildly elevated BP resulted in a significant reduction in their daily sodium intake as well as a reduction in SBP.</p> <p>Trial Registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN01739816">ISRCTN01739816</a></p

Role of salt intake in prevention of cardiovascular disease: controversies and challenges.

Strong evidence indicates that reduction of salt intake lowers blood pressure and reduces the risk of cardiovascular disease (CVD). The WHO has set a global target of reducing the population salt intake from the current level of approximately 10 g daily to 85 categories of food; many other developed countries are following the UK's lead. In developing countries where most of the salt is added by consumers, public health campaigns have a major role. Every country should adopt a coherent, workable strategy. Even a modest reduction in salt intake across the whole population can lead to a major improvement in public health and cost savings