C-reactive protein, inflammation and atherosclerosis: do we really understand it yet?

During the past decade, it has become apparent that atherosclerosis is an inflammatory process. This fact has engendered a great deal of interest in identifying markers which may be detected in the blood that could reflect the state of the underlying inflammation present in the vascular wall. In the current issue Tataru et al. study the relationship between plasma C-reactive protein levels and the severity of atherosclerosis in 1112 male and 299 female survivors of acute myocardial infarction, as well as 326 male and 138 female controls. Patients in the study were divided into groups according to the severity of the manifestations of atherosclerosis. The worse the generalized manifestations of atherosclerosis, the higher the C-reactive protein levels. C-reactive protein was also shown to be higher in smokers and with increasing age. C-reactive protein also correlated with other risk factors for atherosclerosis, which in turn explain a modest amount of the variability in the C-reactive protein values. This paper confirms a number of other studies that have shown a relationship between atherosclerosis and inflammation. This is because C-reactive protein is an acute phase reactant, detectable in the plasma in numerous inflammatory processes. By themselves, such studies do not address the more fundamental nature of the association between inflammation and the pathogenesis of atherosclerosis. It is clear that lipids, oxidation state, mechanical stress, thrombosis, and perhaps even infection participate in the pathogenesis of atherosclerosis. The earliest event is thought to involve oxidative modification of lipoproteins in the subintimal space. These modified lipoproteins elicit an immune-like response in the vessel wall, including stimulation of inflammatory cytokines and expression of vascular cell adhesion molecule-1 (VCAM-1) and the monocyte chemoattractant peptide-1 (MCP-1). The latter two are critical in recruiting monocytes into the subintimal space, where they become lipid-laden foam cells and release large amounts of reactive oxygen species, which in turn further oxidize lipoproteins. These heavily oxidized lipoproteins are avidly taken up by foam cells and are very biologically active. Why do lipoproteins in the subintimal space evoke such an immune response? What does this have to do with C-reactive protein? It is fascinating to note that the antigenic proteins of several microbial agents are lipoproteins. In particular, mycobacterium tuberculosis secretes a 19 kD lipoprotein that stimulates the production of the inflammatory cytokine IL-12 from human monocytes via activation of the Toll receptor. This receptor is present in many organisms, including Drisophila, suggesting that it is a fundamental defence mechanism that has been used by both vertebrates and invertebrates for millions of years. Of note, injection of mice with a heat shock protein of mycobacterium tuberculosis increases the development of atherosclerosis. Thus, it is interesting to speculate that the inflammation observed in atherosclerosis represents a very basic immune response originally designed to defend against invading microorganisms. Also of note, oxidation of lipoproteins is probably an attempt at an adaptive response. Unmodified lipoproteins are taken up via the LDL receptor of macrophages and other cells. This receptor is rapidly down-regulated by the presence of excess amounts of LDL. In contrast, oxidized LDL is taken up by the scavenger receptor, which is not subject to down-regulation. Thus, lipoprotein oxidation permits macrophages to ‘clean-up’ large amounts of lipids from the subintimal space. The problem facing our society in general is that our diet and other risk factors increase the amount of lipoproteins and, in particular, oxidatively modified lipoproteins in the subintimal space, promoting this very basic, and otherwise protective, immunological response. Some of these risk factors, such as diabetes, cigarette smoking, and hormonal influences, especially angiotensin II, increase the oxidative state of the vessel wall, contributing to this cascade by amplifying the oxidation of lipoproteins. Part of this inflammatory response is a loss of the endothelial production of nitric oxide, which results from several mechanisms. One involves downregulation of the endothelial cell nitric oxide synthase mRNA by locally released cytokines and oxidized LDL. A second involves oxidative destruction of nitric oxide by the superoxide anion, produced in excess quantities in several pathological states. Nitric oxide has potent antioxidant and antiinflammatory roles in the blood vessel, and thus the loss of nitric oxide in these various conditions unmasks and even promotes this inflammatory process.