Abstract 134: Hypoxia in Coronary Plaque Enhance Thrombogenic Potential of Activated Macrophages

Abstract

Background: Thrombogenic potential on disrupted atherosclerotic plaque is an important factor on the development of atherothrombosis, and inflammatory stimuli up-regulate thrombogenic factors. We have revealed that arterial glucose metabolism and hypoxia reflect the vascular wall thrombogenicity in rabbit. However, role of inflammation and/or hypoxia on the thrombogenicity in atherosclerotic plaque remain unclear. The present study aims to identify expression of hypoxic/metabolic markers and thrombogenic factors in human coronary plaques and also aims to evaluate the effect of of inflammatory and hypoxic stimuli on thrombogenicity in cultured macrophages. Methods: We immunohistochemically investigated numbers of inflammatory cells and microvessels, and expression of hexokinase (HK)-II, monocarboxylate transportor 4 (MCT4) (hypoxic/metabolic markers), and tissue factor (TF) in human vulnerable coronary plaques (n=22) and stable plaques (n=10). TF expression, procoagulant activity, and lactate production were assessed in THP-1 macrophages stimulated by tumor necrosis factor-α (10ng/mL) and interferon-γ (20ng/mL) under normoxic (21%O 2 ) or hypoxic (1%O 2 ) condition. Results: Numbers of macrophages, HK-II-, MCT4-, TF-immunopositive cells in the vulnerable plaques were significantly larger than those in the stable plaques. Many macrophages expressed HK-II, MCT4, and TF in the plaques. TF expression and procoagulant activity in the cultured macrophages were increased by the inflammatory stimuli, and were enhanced by hypoxia. The hypoxic condition also increased HK-II expression and lactate production, but the inflammatory stimuli did not affect them. Conclusion: Hypoxia in coronary plaque may enhance thrombogenic potential of macrophages activated by inflammatory stimuli.