Abstract
Atherosclerotic lesions are often hypoxic and exhibit elevated lactate concentrations and local acidification of the extracellular fluids. The acidification 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 proinflammatory cytokines from macrophages through activation of the inflammasome pathway. Acidity enhances the proteolytic, lipolytic, and oxidative modifications of LDL and other apoB-containing lipoproteins, and strongly increases their affinity 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 amplifies the proatherogenic and proinflammatory processes involved in atherogenesis.
Highlights
Atherosclerotic lesions are often hypoxic and exhibit elevated lactate concentrations and local acidification of the extracellular fluids
By virtue of its ability to enhance extracellular and intracellular lipid accumulation and to promote proinflammatory processes in macrophages, extracellular acidity has emerged as a novel and potentially crucial element of atherogenesis
In contrast to the rather straightforward scenario of a proatherogenic role of acidity on intimal accumulation of cholesterol derived from apoB- 100-containing lipoproteins, HDL metabolism in the acidic intimal fluid appears to be complex and unpredictable in its potential outcomes
Summary
Tissue hypoxia and acidification may be linked via enhancement of glycolytic cellular metabolism at the hypoxic areas. Several types of activated immune cells, including the macrophages abundant in atheromas, favor energy production by glycolysis even in a normoxic environment [reviewed in [8, 27]] This phenomenon of aerobic glycolysis, known as the Warburg effect, was first described in cancer cells by the world-renowned biochemist Otto Warburg [28]. The rationale behind the strong induction of aerobic glycolysis in activated macrophages and other immune cells most likely lies in the strong induction of various biosynthetic pathways and proliferation in these cells; glycolysis is a rapid source of ATP, but a high glycolytic rate promotes accumulation of glycolytic intermediates that are mainly fed into the pentose phosphate pathway for the production of amino acids, nucleotides, and NADPH [8]. Both increased lactate concentrations [26] and extracellular acidification [22] are observed in atherosclerotic lesions
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