Acidifi cation of the intimal fl uid: The perfect storm for atherogenesis

Abstract

Atherosclerotic lesions are often hypoxic and exhibit elevated lactate concentrations and local acidifi cation of the extracellular fl uids. The acidifi cation may be a consequence of the abundant accumulation of lipid-scavenging macrophages in the lesions. Activated macrophages have a very high energy demand and they preferentially use glycolysis for ATP synthesis even under normoxic conditions, resulting in enhanced local generation and secretion of lactate and protons. In this review, we summarize our current understanding of the effects of acidic extracellular pH on three key players in atherogenesis: macrophages, apoB-containing lipoproteins, and HDL particles. Acidic extracellular pH enhances receptor-mediated phagocytosis and antigen presentation by macrophages and, importantly, triggers the secretion of proinfl ammatory cytokines from macrophages through activation of the infl ammasome pathway. Acidity enhances the proteolytic, lipolytic, and oxidative modifi cations of LDL and other apoB-containing lipoproteins, and strongly increases their affi nity for proteoglycans, and may thus have major effects on their retention and the ensuing cellular responses in the arterial intima. Finally, the decrease in the expression of ABCA1 at acidic pH may compromise cholesterol clearance from atherosclerotic lesions. Taken together, acidic extracellular pH amplifi es the proatherogenic and proinfl ammatory processes involved in atherogenesis.