Interplay between CRP, Atherogenic LDL, and LOX-1 and Its Potential Role in the Pathogenesis of Atherosclerosis Nicole Stancel, 1† Chih-Chieh Chen, 2,3† Liang-Yin Ke, 2,4,5 Chih-Sheng Chu, 2,6,7 Jonathan Lu, 1 Tatsuya Sawamura, 8* and Chu-Huang Chen 1,2,4,9,10,11* BACKGROUND: Studies have shown that the classic acute-phase protein C-reactive protein (CRP) has pro- inflammatory effects on vascular cells and may play a causal role in the pathogenesis of coronary artery dis- ease. A growing body of evidence has suggested that interplay between CRP, lectin-like oxidized LDL receptor-1 (LOX-1), and atherogenic LDL may un- derlie the mechanism of endothelial dysfunction that leads to atherosclerosis. CONTENT: We review the biochemical evidence for an association of CRP, LOX-1, and either oxidized LDL (OxLDL) or electronegative L5 LDL with the pathogen- esis of coronary artery disease. Artificially oxidized OxLDL has been studied extensively for its role in atherogenesis, as has electronegative L5 LDL, which is present at increased levels in patients with increased car- diovascular risks. OxLDL and L5 have been shown to stimulate human aortic endothelial cells to produce CRP, indicating that CRP is synthesized locally in the endothe- lium. The ligand-binding face (B-face) of CRP has been shown to bind the LOX-1 scavenger receptor and in- crease LOX-1 expression in endothelial cells, thereby promoting the uptake of OxLDL or L5 by LOX-1 into endothelial cells to induce endothelial dysfunction. SUMMARY: CRP and LOX-1 may form a positive feed- back loop with OxLDL or L5 in atherogenesis, whereby increased levels of atherogenic LDL in patients with car- diovascular risks induce endothelial cells to express CRP, which may in turn increase the expression of LOX-1 to promote the uptake of atherogenic LDL into endothelial cells. Further research is needed to confirm a causal role for CRP in atherogenesis. © 2015 American Association for Clinical Chemistry One of the most extensively studied predictors of cardio- vascular events is C-reactive protein (CRP), 12 a classic acute-phase protein widely used in the clinical setting as a biomarker of systemic inflammation. Plasma concentra- tions of CRP have been shown to have a strong predictive value for cardiovascular events, possibly stronger than that of standard cardiovascular disease risk factors, in- cluding LDL (1). According to current guidelines of the American College of Cardiology Foundation/American Heart Association, CRP may be useful in the selection of patients for statin therapy or for cardiovascular risk as- sessment in intermediate-risk patients (2). Findings in- dicating that CRP may be a powerful predictive bio- marker for cardiovascular events have raised equally important questions regarding whether CRP has a direct role in the pathogenesis of cardiovascular diseases. Stud- ies from various laboratories have shown that CRP has proinflammatory effects and may play a causal role in endothelial dysfunction that leads to atherosclerosis. CRP has been found to interact with many proteins, including lectin-like oxidized LDL receptor-1 (LOX-1) (3), C1q (4), oxidized low-density lipoprotein (OxLDL) (5), class-A scavenger receptor (SR-A) (6), and Fc re- ceptors (FcRs) (7), but these interactions and their con- tributions to atherosclerotic disease progression have not 1 Department of Vascular and Medicinal Research, Texas Heart Institute, Houston, TX; 2 Center for Lipid Biosciences, Kaohsiung Medical University (KMU) Hospital, KMU, Kaohsiung, Taiwan; 3 Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan; 4 Lipid Science and Aging Research Center, KMU, Kaoh- siung, Taiwan; 5 Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, KMU, Kaohsiung, Taiwan; 6 Department of Internal Medicine, KMU Hospital, Kaohsiung, Taiwan; 7 Faculty of Medicine, College of Medicine, KMU, Kaohsi- ung, Taiwan; 8 Department of Physiology, Shinshu University School of Medicine, Ma- tsumoto, Nagano, Japan; 9 Cardiovascular Research Center, China Medical University (CMU) Hospital, CMU, Taichung, Taiwan; 10 Section of Cardiovascular Research, Depart- ment of Medicine, Baylor College of Medicine, Houston, TX; 11 Current affiliation: New York Heart Research Foundation, Mineola, NY. † Nicole Stancel and Chih-Chieh Chen contributed equally to the work, and both should be considered as first authors. * Address correspondence to: C.-H.C. at Vascular and Medicinal Research, Texas Heart Institute, 6770 Bertner Ave., Houston, Texas 77030. Fax 832-355-9333; e-mail cchen@texasheart.org. T.S. at Department of Physiology, Shinshu University School of Medicine, Matsumoto, Na- gano, Japan. Fax +81-263-365149; e-mail t-sawamura@umin.ac.jp. Received June 10, 2015; accepted September 30, 2015. Previously published online at DOI: 10.1373/clinchem.2015.243923 © 2015 American Association for Clinical Chemistry 12 Nonstandard abbreviations: CRP, C-reactive protein; LOX-1, lectin-like oxidized low- density lipoprotein receptor-1; OxLDL, oxidized LDL; SR-A, class-A scavenger receptor; FcR, Fc receptor; CAD, coronary artery disease; SAP, serum amyloid P component; LAB, LOX-1 ligand containing apolipoprotein B; L5%, percent L5 of total LDL; IL, inter- leukin; TNF-, tumor necrosis factor-; MRM-MS, multiple-reaction monitoring mass spectrometry; LPC, lysophosphatidylcholine; LDL-, electronegative LDL. Clinical Chemistry 62:2 320–327 (2016) Mini-Review 320 Downloaded from https://academic.oup.com/clinchem/article/62/2/320/5611849 by guest on 05 August 2022