S-Thiolation Targets Albumin in Heart Failure

Abstract

Human serum albumin (HSA) is associated with several physiological functions, such as maintaining oncotic pressure and microvascular integrity, among others. It also represents the major and predominant antioxidant in plasma due to the presence of the Cys34 sulfhydryl group.In this study, we assessed qualitative and quantitative changes in HSA in patients with heart failure (HF) and their relationship with the severity of the disease. We detected by means of mass spectrometry a global decrease of the HSA content in the plasma of HF patients in respect to control subjects, a significant increase of thio-HSA with a concomitant decrease in the reduced form of albumin. Cysteine and, at a lesser extent, homocysteine represent the most abundant thiol bound to HSA. A strong inverse correlation was also observed between cysteine-HSA and peak VO2/kg, an index of oxygen consumption associated with HF severity. Moreover, in HL-1 cardiomyocytes incubated with H2O2, we showed a significant decrease of cell viability in cells treated with thio-HSA in respect to restored native-HSA. In conclusion, we found for the first time that S-thiolation of albumin is increased in the plasma of HF patients and induced changes in the structure and antioxidant function of HSA, likely contributing to HF progression.

Serum Albumin Redox States: More Than Oxidative Stress Biomarker

“…Still, when considering the incompatibility of the use of reducing agents with the analyses of mixed disulfides on Cys34, the addition of other analytical methods that complement bottom-up proteomics would be more desirable. Brioschi et al analyzed small thiol compounds originally bound to serum ALB as mixed disulfides [ 13 ]. These compounds were released by treating serum ALB with a reducing agent tris(2-carboxyethyl)phosphine, and they were then derivatized with 4-[2-(dimethylamino)ethylaminosulfonyl]-7-chloro-2,1,3-benzoxadiazole (DAABD-Cl).…”

“…Binding affinities for lipid mediators also differs between reduced and oxidized serum ALB isoforms; proatherosclerotic lipids such as lysophosphatidylcholine and lysophosphatidic acid have higher affinities for oxidized ALB isoform, while anti-atherosclerotic mediators derived from eicosapentaenoic acid and docosahexaenoic acid possess higher affinities for reduced ALB isoform [ 12 ]. Furthermore, ALB oxidation (the increased HNA-1 level) was accompanied by decreased anti-oxidative activity as measured by a total radical-trapping antioxidant parameter assay [ 13 ]. The oxidation of biological components such as proteins, lipids, carbohydrates and DNA proceeds when anti-oxidative potential is attenuated.…”

Oxidized Albumin as a Mediator of Kidney Disease

“…In healthy young persons, ≈70% and ≈30% of HSA presents Cys34 as a free sulfhydryl group and as a reversible mixed disulfide with other thiols of low molecular weight, respectively [ 109 ]. On the other hand, Brioschi et al found that S-thiolation of HSA was augmented in the plasma of heart failure patients, particularly in high severity cases (class III and class IV according to the New York Heart Association classification) [ 110 ]. In addition, the authors found that S-thiolated HSA correlated with deficient antioxidant activity in plasma, suggesting that S-thiolation promoted changes in HSA at the structure and function level [ 110 ].…”

“…On the other hand, Brioschi et al found that S-thiolation of HSA was augmented in the plasma of heart failure patients, particularly in high severity cases (class III and class IV according to the New York Heart Association classification) [ 110 ]. In addition, the authors found that S-thiolated HSA correlated with deficient antioxidant activity in plasma, suggesting that S-thiolation promoted changes in HSA at the structure and function level [ 110 ]. Similar results were found in eight end-stage renal disease patients with at least 3 months of hemodialysis, observing an increase in pre-dialysis S-thiolation levels of HSA compared to control patients.…”

Crosslinking of human plasma C-reactive protein to human serum albumin via disulfide bond oxidation

“…quinones and unsaturated aldehydes) [ [31] , [32] , [33] , [34] , [35] ]. Increased levels of these modified forms are associated with smoking, aging, and multiple acute and chronic diseases [ [36] , [37] , [38] , [39] ].…”