title: Acidification of the intimal fluid: the perfect storm for atherogenesis.
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.
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Katariina
authors.initials: K
authors.lastname: Öörni
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Rajamäki
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Su Duy
authors.initials: SD
authors.lastname: Nguyen
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Katariina
authors.initials: K
authors.lastname: Lähdesmäki
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Riia
authors.initials: R
authors.lastname: Plihtari
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Lee-Rueckert
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
mesh_terms: D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D010740:Phospholipases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D017539:Tunica Intima / Q000378:metabolism*
chemical_list: D001053:Apolipoproteins; D008074:Lipoproteins; D011509:Proteoglycans; D010740:Phospholipases
keywords: apolipoproteins; high density lipoprotein; inflammasome; inflammation; lipids/efflux; lipoproteins • macrophages/monocytes; low density lipoprotein; phospholipases; proteoglycans