Abstract
C-reactive protein (CRP) is a pentameric molecule made up of identical monomers. CRP can be seen in three different forms: native pentameric CRP (native CRP), non-native pentameric CRP (non-native CRP), and monomeric CRP (mCRP). Both native and non-native CRP execute ligand-recognition functions for host defense. The fate of any pentameric CRP after binding to a ligand is dissociation into ligand-bound mCRP. If ligand-bound mCRP is proinflammatory, like free mCRP has been shown to be in vitro, then mCRP along with the bound ligand must be cleared from the site of inflammation. Once pentameric CRP is bound to atherogenic low-density lipoprotein (LDL), it reduces both formation of foam cells and proinflammatory effects of atherogenic LDL. A CRP mutant, that is non-native CRP, which readily binds to atherogenic LDL, has been found to be atheroprotective in a murine model of atherosclerosis. Thus, unlike statins, a drug that can lower only cholesterol levels but not CRP levels should be developed. Since non-native CRP has been shown to bind to all kinds of malformed proteins in general, it is possible that non-native CRP would be protective against all inflammatory states in which host proteins become pathogenic. If it is proven through experimentation employing transgenic mice that non-native CRP is beneficial for the host, then using a small-molecule compound to target CRP with the goal of changing the conformation of endogenous native CRP would be preferred over using recombinant non-native CRP as a biologic to treat diseases caused by pathogenic proteins such as oxidized LDL.
Highlights
C-reactive protein (CRP) is a pentamer of identical subunits which functions in two different structural states, as native pentameric CRP in normal physiological environment and as non-native pentameric CRP in localized pathological and inflammatory environments [1,2,3,4,5,6,7]
Since foam cell formation is inhibited whenever CRP is complexed with modified low-density lipoprotein (LDL) such as CRP-enzymatically-modified LDL (E-LDL) and monomeric CRP (mCRP)-acetylated LDL, it has been proposed that if each LDL molecule retained in the arterial wall becomes CRP-bound, the development of atherosclerosis should be retarded [58]
CRP does not show an effect on the development of atherosclerosis likely because the inflammatory microenvironment in the arterial wall in animal models of atherosclerosis may not be appropriate in terms of pH and redox conditions and, the structure of CRP remains unchanged
Summary
C-reactive protein (CRP) is a pentamer of identical subunits which functions in two different structural states, as native pentameric CRP (native CRP) in normal physiological environment and as non-native pentameric CRP (non-native CRP) in localized pathological and inflammatory environments [1,2,3,4,5,6,7]. Since foam cell formation is inhibited whenever CRP is complexed with modified LDL such as CRP-E-LDL and mCRP-acetylated LDL, it has been proposed that if each LDL molecule retained in the arterial wall becomes CRP-bound, the development of atherosclerosis should be retarded [58].
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