C-Terminally Truncated Apolipoprotein A1 Glutamate Residue 243 Is a Biomarker for Oxidative Stress in Coronary Artery Disease and Chronic Kidney Disease

Abstract

High density lipoprotein (HDL) oxidation is a potential biomarker for coronary artery disease (CAD) severity. Methionine sulfoxidation, tyrosine chlorination and C-terminal truncation are Apo A- I modifications that inactivate HDL and lead to pro-oxidant action. We hypothesize that C-terminal truncation of apolipoprotein A1 glutamate residue 243 (Apo A-I Des-Q243) is a byproduct of a protease, such as a matrix metalloprotease (MMP), and it is associated with the presence and severity of coronary artery disease and chronic kidney disease (CKD). We enrolled 103 patients presenting for evaluation of chest pain in this cross-sectional study at Maricopa Medical Center. Plasma and serum samples were collected, processed, and transferred to Arizona State University (ASU) Biodesign Institute for high pressure liquid chromatography-mass spectrometry (HPLC-MS). A statistical analysis was conducted with a spearman’s coefficient, two-tailed linear regression and multivariate analysis of the relative fractional abundance (RFA) of Apo A-I Des-Q243 and clinical variables. Multivariate analysis revealed significantly reduced levels of Apo A-I Des-Q243 in the presence of male gender (-1.5%, P=0.035), atrial fibrillation (-2.8%, P=0.04), and ACEi/ARB use (-2.4%, P=0.001). Additionally, a diagnosis of CKD (2.3%, P=0.037) and the presence of four (9.6%, P=0.005) or five (4.7%, P=0.045) coronary stents, regardless of vessel location, were associated with significantly increased levels of Apo A-I Des-Q243. American Indian/Alaskan race as compared to Caucasian race (Plasma -5.8%, 95% CI -9.9- -1.8%, P=0.005; Serum -4.6%, 95% CI -8.5- -0.8%, P=0.02), and the eGFR (Plasma ρ=-0.024, P=0.014, Serum ρ=-0.291, P=0.003) only reached significance in the linear regression and spearman’s correlation analysis respectively. Apo A-I Des-Q243 is elevated in patients with multiple coronary stents, and thus may be contributing to vascular inflammation and plaque formation. Furthermore, Apo A-I Des-Q243 is elevated in CKD and is directly correlated with its severity as determined by eGFR. These findings highlight the renin-aldosterone system’s (RAS) role in HDL oxidation and the anti-oxidant action of ACEi/ARBs. Apo A-I Des-Q243 appears to be an important link between CAD and CKD and is a promising biomarker that warrants further study.