Potential to inhibit growth of atherosclerotic plaque development through modulation of macrophage neopterin/7,8‐dihydroneopterin synthesis

Abstract

The rise in plasma neopterin observed with increasing severity of vascular disease is a strong indicator of the inflammatory nature of atherosclerosis. Plasma neopterin originates as the oxidation product of 7,8-dihydroneopterin secreted by g-interferon stimulated macrophages within atherosclerotic plaques. Neopterin is increasingly being used as a marker of inflammation during clinical management of patients with a range of disorders including atherosclerosis. Yet the role of 7,8-dihydroneopterin/neopterin synthesis during the inflammatory process and plaque formation remains poorly understood and controversial. This is partially due to the unresolved role oxidants play in atherosclerosis and the opposing roles of 7,8-dihydroneopterin/neopterin. Neopterin can act as pro-oxidant, enhancing oxidant damage and triggering apoptosis in a number of different cell types. Neopterin appears to have some cellular signalling properties as well as being able to chelate and enhance the reactivity of transition metal ions during Fenton reactions. In contrast, 7,8-dihydroneopterin is also a radical scavenger, reacting with and neutralizing a range of reactive oxygen species including hypochlorite, nitric oxide and peroxyl radicals, thus protecting lipoproteins and various cell types including macrophages. This has led to the suggestion that 7,8-dihydroneopterin is synthesized to protect macrophages from the oxidants released during inflammation. The oxidant/ antioxidant activity observed in vitro appears to be determined both by the relative concentration of these compounds and the specific chemistry of the in vitro system under study. How these activities might influence or modulate the development of atherosclerotic plaque in vivo will be explored in this review.

Pig Bone Marrow-Derived Macrophages Resemble Human Macrophages in Their Response to Bacterial Lipopolysaccharide

“…In most respects, the pig BMDM studied in this work resembled human monocyte-derived macrophages more closely than mouse BMDM. All three species induce the enzyme GCH1, which generates the cofactor tetrahydrobiopterin (BH4), and the by-product neopterin, which is a common marker of inflammation (64). Like human macrophages, and in keeping with earlier findings on other pig macrophage populations, pig BMDM did not produce NO, nor did they induce arginine-metabolizing genes or CAT2 in response to LPS (44,45).…”

Neopterin and 7,8-dihydroneopterin are generated within atherosclerotic plaques

“…However, many plaques displayed a combination of these characteristics over their length. Figure 2E), while plaque 27 had extremely high levels in four distinct sections [3][4][5][6], which were separated by regions of low levels (Figure 2A). The highest total neopterin level measured in the study was 18 nmol/g of plaque tissue and was found in a small bifurcation region labelled Section 3 of plaque 27 ( Figures 1A3 and 2A).…”

“…Our previous analysis of atherosclerotic plaques removed from carotid arteries showed neopterin concentrations ranging from 0.72 to 2.34 μmol/L within the whole plaque [15]. Within one individual plaque that we sectioned, we reported large variations in neopterin concentration ranging from 0.4 to 2.2 nmol/g of wet tissue [6]. Based on these limited data, there appears to be a large range of neopterin concentrations both between plaques and within an individual plaque.…”

“…HOCl reacts extremely rapidly with 7,8-dihydroneopterin to generate neopterin [20,21], suggesting that a significant amount of the neopterin measured in serum and urine may be from the scavenging of HOCl released by neutrophils and macrophages during inflammation. These in vitro studies have led to the proposal that 7,8-dihydroneopterin is generated by macrophages to protect these cells from oxidants generated during inflammation [6,13,22,23].…”

“…The inflammatory nature of the disease is highlighted by the correlation between plasma neopterin levels and increasing severity of cardiovascular disease [1][2][3][4]. Neopterin is a highly fluorescent pterin compound, whose measurement in urine and plasma has been extensively used as a marker of inflammation in a wide number of inflammatory conditions including vascular disease [5,6]. During inflammation, γ-interferon released by T cells stimulates the enzymatic breakdown of guanosine-5′-triphosphate to 7,8-dihydroneopterin in human macrophages.…”