Cysteinylated and glycated human serum albumin levels are increased in human heart failure

Abstract

Cysteinylated human serum albumin (Cys-HSA) is a post-translational modification of human serum albumin (HSA) where the sulfhydryl group (SH) of cysteine in position 34 (Cys34) becomes oxidized by a cysteine [1] and this oxidation easily occurs when exposed to oxidative stress [2]. The degree of oxidized Cys34 in HSA is correlated with oxidative stress related pathological conditions [3]. Indeed, increased Cys-HSA levels have been detected in patients undergoing end stage renal disease [4], coronary artery disease [2], chronic liver disease or diabetes mellitus [3] as well as in pregnant women with intrauterine growth restriction [5]. Functional loss of HSA due to post-translational modification could influence homeostasis, which may contribute to the progression of chronic diseases. For example, Oettl et al. reported that, in advanced liver disease, oxidative damage impairs the binding properties of HSA resulting in increased tissue distribution of toxic endogenous compounds, and thus enhancing the risk of tissue damage related to complications [6]. Similarly, the loss of significant oxidant buffering capacity of HSA due to Cys-HSA may lead pregnancy complications such as intrauterine growth restriction [5]. In this study we examined for the first time the extent of Cys-HSA in plasma of patients with heart failure [NYHA class III and IV (n class III =10, n class IV = 10)] compared with healthy subjects (n=11) by using a direct infusion ESI-MS. Blood samples were collected in citrate tubes and centrifuged immediately after collection. Plasma fraction was stored at -80 °C. Before the analysis, plasma samples were diluted 1:200 in water containing 50% acetonitrile and 0.1% formic acid and infused into a triple quadrupole mass spectrometer (Xevo TQ-S from Waters). The relative content of the HSA isoforms (Cys-HSA and glycated-HSA) were determined by measuring their relative intensities. Results showed a significant increase of Cys-HSA in heart failure (HF) patients (13.11%±5 and 17.31%±3.6 for NYHA III and IV, respectively) with respect to age-matched healthy subjects (9.87%±3). Furthermore, the levels of glycated-HSA were higher in HF patients (7.72%±1.49 and 8.04%±0.85, for NYHA III and IV, respectively) in comparison with age-matched healthy subjects (6.535%+0.54). Finally, HF patients showed a significant decrease in the total level of HSA as expected [7]. In conclusion, this study revealed an increased level of cysteinylation and glycation of HSA in patients with HF expanding the current knowledge that different residues on HSA can undergo certain post-translational modifications in specific environments in oxidative stress-related diseases. Future studies will establish the utility of monitoring the redox status of Cys34 in HSA as a marker for oxidative stress in HF and its potential role in the onset and progression of the disease. Finally, since HSA has an established role as a blood stream carrier, it will be interesting and exciting to test how these modifications can affect drug delivery of various pharmacological treatments in HF.