Cysteine/cystine redox signaling in cardiovascular disease

Abstract

Extracellular thiol/disulfide redox environments are highly regulated in healthy individuals. The major thiol/disulfide redox couple in human plasma is cysteine (Cys) and its disulfide form, cystine (CySS). Oxidation of this redox couple measured as a more positive steady-state redox potential (Eh) is associated with risk factors for cardiovascular disease (CVD), including aging, smoking, obesity, and alcohol abuse. Rodent and vascular cell studies show that extracellular redox state of Cys/CySS (EhCySS) can play a vital role in controlling CVD through proinflammatory signaling. This inflammatory signaling is regulated by cell surface protein redox state and involves mitochondrial oxidation, nuclear factor-κB activation, and elevated expression of genes for monocyte recruitment to endothelial cells. Gene array and proteomics studies reveal the global nature of redox effects, and different cell types, e.g., endothelial cells, monocytes, fibroblasts, and epithelial cells, show cell-specific redox responses with different phenotypic traits, e.g., proliferation and apoptosis, which can contribute to CVD. The critical nature of the proinflammatory redox signaling and cell biology associated with EhCySS supports the use of plasma levels of Cys, CySS, and EhCySS as key indicators of vascular health. Plasma redox state-based pharmacologic interventions to control or improve EhCySS may be effective in preventing CVD onset or progression.

Inhibition of thiol isomerase activity diminishes endothelial activation of plasminogen, but not of protein C

“…The extracellular redox environment is recognised as an important regulator of both platelet function [34,35] and endothelial biology [36] and changes in plasma redox state occur in conditions characterised by increased cardiovascular risk [37]. Our findings suggest that alteration in fibrinolysis may be a further aspect of deranged vascular biology in these conditions.…”

Serum free sulfhydryl status is associated with patient and graft survival in renal transplant recipients

“…4 High levels of free sulfhydryl groups (R-SH) may be a reflection of a favorable redox status since they avidly interact with ROS and other reactive species. 5 In healthy individuals, the concentrations of serum protein thiols are highly regulated 6 and form part of an intricate redox network that underpins human adaptation to nutritional, metabolic and environmental challenges. 7 Conditions promoting oxidative stress result in the oxidation of free sulfhydryl groups to their corresponding disulfides, which is associated with risk for CVD.…”

“…7 Conditions promoting oxidative stress result in the oxidation of free sulfhydryl groups to their corresponding disulfides, which is associated with risk for CVD. 6 The extracellular redox status influences CVD through proinflammatory signaling, which involves mitochondrial oxidation, nuclear factor-κB activation and elevated expression of genes for monocyte recruitment to endothelial cells. 6 While the thiol/disulfide status of glutathione and cysteine, for example, are acknowledged readouts of oxidative stress their analytical determination at the prevailing low concentrations in plasma or serum can be challenging and requires specific detection techniques such as high-pressure liquid chromatography or mass spectrometry not available to all laboratories.…”

“…6 The extracellular redox status influences CVD through proinflammatory signaling, which involves mitochondrial oxidation, nuclear factor-κB activation and elevated expression of genes for monocyte recruitment to endothelial cells. 6 While the thiol/disulfide status of glutathione and cysteine, for example, are acknowledged readouts of oxidative stress their analytical determination at the prevailing low concentrations in plasma or serum can be challenging and requires specific detection techniques such as high-pressure liquid chromatography or mass spectrometry not available to all laboratories. Moreover, at present there is no consensus about the significance of specific low-molecular-weight or protein thiols for disease protection and many low-abundant thiols are prone to rapid artificial oxidation.…”

Antioxidant status and glutathione redox potential of erythrocytes in patients with acute coronary syndrome

“…Установлено, что редокс-потенциал плаз-мы крови (2GSH/GSSG, цистеин/цистин) явля-ется прогностическим тестом возникновения патологии сердечно-сосудистой системы [16], тогда как роль клеточного редокс-потенциала, в частности у эритроцитов, изучена недостаточно. Особенно это относится к острому коронарному синдрому (ОКС), при котором манифестируют проявления окислительного стресса на фоне системного воспаления.…”