Therapeutic potential of phosphoethanolamine-bound C-reactive protein in atherosclerosis

Abstract

Three papers published in the year 2008 from my laboratory reported experiments and data indicating the therapeutic potential of phosphoethanolamine-bound C-reactive protein (PEt-bound CRP) in atherosclerosis. The small-molecule compound PEt, which binds to CRP, could in itself be of therapeutic value. The first paper described the capability of PEt-bound CRP to capture native low-density lipoprotein (LDL) cholesterol in human serum [1]. The second paper described the potency of PEt-bound CRP to bind to a modified form of LDL called enzymatically-modified LDL (E-LDL). Although CRP alone could bind to E-LDL, the PEt-bound CRP was much more potent than unbound CRP in binding to E-LDL [2]. This paper also reported a previously unknown function of CRP. CRP, once bound to E-LDL, prevented the formation of E-LDL-loaded macrophage foam cells. The third paper further emphasized the importance of PEt-bound CRP and presented a review of the literature on the connection between CRP and atherosclerosis [3]. CRP, also known as high-sensitivity CRP or hsCRP, is a serum protein which is used as a marker of systemic inflammation [see CRP reviews 3-7, and the references cited in 3, 4]. CRP is associated with risk of atherosclerosis; however, recent data suggest that the association of CRP with atherosclerosis may not be causal [8]. In 1982, it was shown that under certain experimental conditions CRP interacted with LDL [9]. Since then CRP was suspected to play a role in atherosclerosis. CRP was also found deposited and co-localized with LDL and macrophages in human atherosclerotic lesions. Discovering the functions of CRP in atherosclerosis quickly became a hot subject for research. Atherosclerosis is a heart disease caused by the deposition and subsequent modification of LDL in artery walls. Atherogenic LDL, which includes modified forms of LDL produced by oxidation and proteolysis of LDL, enters macrophages to form foam cells. The LDL-loaded macrophage foam cells contribute to the development of atherosclerosis which leads to myocardial infarction. To prevent atherosclerosis, LDL can be targeted therapeutically at two locations: the native LDL found mostly in the circulation and the atherogenic LDL located mostly in the artery walls.