Mechanisms and Inhibitors of Macrophage Cell Death Within Advance Atherosclerotic Plaques

Abstract

The formation of oxidised low-density lipoproteins (oxLDL) within the artery wall is a key driver in the development of advanced atherosclerotic plaques. OxLDL has usually been thought to cause macrophage apoptosis via the absorption of cytotoxic oxidation products within oxLDL. We have shown that oxLDL also triggers a rapid necrotic cell death via activation of the superoxide generating complex NADPH oxidase (NOX). The excess oxidant generation causes oxidative loss of intracellular glutathione and the inactivation of thiol-dependent metabolic enzymes. The resulting loss of ATP generation triggers macrophage cell death but oxidative loss of thiol-dependent caspases means the death mechanism is necrotic rather than apoptopic [ [1] FEBS Letters 2004;578:169. Google Scholar ]. Both oxLDL formation and oxLDL cytotoxicity may be held in check within the artery wall through macrophage generated antioxidants. Interferon-γ stimulation of macrophages induces the synthesis and release of 7,8-dihydroneopterin, a potent inhibitor of macrophage oxidation of LDL2, and oxLDL cytotoxicity in macrophages [ 2 Antioxidants and Redox Signalling 2010;13:1525–1534. Google Scholar , 3 British Journal of Pharmacology 2008;153:627– 635. Google Scholar ]. Plasma levels of neopterin, the oxidised product of 7,8-dihydroneopterin, are highly correlated with increasing severity of patients atherosclerotic burden and have been measured with atherosclerotic plaques. 7,8-Dihydroneopterin was found to inhibit oxLDL-induced macrophage necrosis by scavenging the NOX-generated intracellular oxidants. The data suggest that the failure or overwhelming of the 7,8- dihydroneopterin protection mechanism may be a contributing factor to the growth of the necrotic core within atherosclerotic plaques.