No Reduction of Atherosclerosis in C-reactive Protein (CRP)-deficient Mice

Abstract

C-reactive protein (CRP), a phylogenetically highly conserved plasma protein, is the classical acute phase reactant in humans. Upon infection, inflammation, or tissue damage, its plasma level can rise within hours >1000-fold, providing an early, nonspecific disease indicator of prime clinical importance. In recent years, another aspect of CRP expression has attracted much scientific and public attention. Apart from transient, acute phase-associated spikes in plasma concentration, highly sensitive measurements have revealed stable interindividual differences of baseline CRP values in healthy persons. Strikingly, even modest elevations in stable baseline CRP plasma levels have been found to correlate with a significantly increased risk of future cardiovascular disease. These observations have triggered intense controversies about potential atherosclerosis-promoting properties of CRP. To directly assess potential effects of CRP on atherogenesis, we have generated CRP-deficient mice via gene targeting and introduced the inactivated allele into atherosclerosis-susceptible ApoE−/− and LDLR−/− mice, two well established mouse models of atherogenesis. Morphometric analyses of atherosclerotic plaques in CRP-deficient animals revealed equivalent or increased atherosclerotic lesions compared with controls, an experimental result, which does not support a proatherogenic role of CRP. In fact, our data suggest that mouse CRP may even mediate atheroprotective effects, adding a cautionary note to the idea of targeting CRP as therapeutic intervention against progressive cardiovascular disease.

Hyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistance

“…(17). Consistent with previous reports (23,24), we found that neither plasma CRP nor SAP was elevated by diet-induced obesity in mice (Supplemental Figure 7, A and B). However, since SAP is the acute-phase reactant pentraxin in mice and CRP is not (25,26), and, as such, SAP abundance may change earlier during the genesis of obesity, we compared the development of obesity-induced insulin resistance in SAP +/+ with that of SAP -/-mice.…”

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

“…Today, little is known about the in vivo effects of mCRP, partially due to lack of suitable animal models. In this context, Teupser et al could show that CRP-deficient mice developed atherosclerosis to the same degree as the control group (60). Neither the reduction of CRP serum concentration nor its complete absence resulted in a significant reduction of atherosclerotic lesions in the brachiocephalic arteries and aortic roots in two distinct mouse models of atherogenesis including a morphometric analysis of 240 animals.…”

Molecular Biology of Atherosclerosis

“…LOX-1 is yet another PAMP-recognizing receptor with a key role in innate immunity (728), being activated by certain gram-positive and gram-negative bacteria, apoptotic bodies, senescent red blood cells, activated white blood cells (WBC) and platelets, advanced glycation end-products (AGEs), lysolecithin, and C-reactive protein (CRP) (561,1621). Note, however, that transgenic CRP overexpression studies and a recently reported CRP knockout have failed to demonstrate any proatherogenic effect for CRP (see TABLE 9) (1778), consistent with the lack of causal effects in human "Mendelian randomization" studies (474).…”