Comprehensive proteomics of monocytes indicates oxidative imbalance functionally related to inflammatory response in chronic kidney disease-related atherosclerosis

Abstract

Atherosclerosis-induced cardiovascular events are the leading cause of mortality in chronic kidney disease (CKD) patients. Monocytes are involved in the formation of atherosclerotic plaques and mediate in the overproduction of ROS, promoting inflammation and oxidative stress. However, the relationship between monocytes, inflammation, and oxidative status in CKD-associated atherosclerosis has not been thoroughly investigated. Monocytes and plasma derived from two groups of CKD patients with varying degrees of atherosclerosis and two groups of patients with cardiovascular disease (CVD) and non-CKD atherosclerosis were analyzed. This study was designed to perform a comprehensive proteomic analysis of monocytes in combination with functional bioinformatics. In addition, a targeted investigation of oxidative stress- and inflammatory-related factors to explore CKD-associated atherosclerosis was applied. Dysregulation of proteins involved in lipid oxidation, cell survival, ROS synthesis and metabolism, and inflammatory responses has been revealed. The characteristic disturbances in the monocyte proteome changed with the progression of CKD. A closer examination of oxidative stress’s triggers, mediators, and effects on protein and lipid levels showed alterations in the oxidative imbalance between CKD and CVD. CKD monocytes demonstrated a significant increase of oxidized glutathione without changing the level of its reduced form. Evaluation of enzymatic antioxidants, sources of ROS, and modifications caused by ROS also revealed significant alterations between the study groups. In CKD, inflammation and oxidative imbalance correlated and drove each other. However, in CVD, oxidative stress-related factors were associated with each other but not to inflammatory proteins. Moreover, lipid abnormalities were more specific to classical CVD and unrelated to CKD. Such a comprehensive characterization of monocytes and oxidative stress in CKD and CVD patients has never been presented so far. Obtained results support the involvement of distinct mechanisms underlying the acceleration of atherosclerotic and non-atherosclerotic CKD.