This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 29/10/1664    most recent ATVBAHA.109.194043v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Deguchi, J.-o Articles by Aikawa, M. PubMed PubMed Citation Articles by Deguchi, J.-o Articles by Aikawa, M.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1664.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Chronic Hypoxia Activates the Akt and β-Catenin Pathways in Human Macrophages

Jun-o Deguchi; Hiroyuki Yamazaki; Elena Aikawa; Masanori Aikawa

From the Cardiovascular Division, Department of Medicine (J.D., H.Y., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and the Department of Radiology (E.A.), Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass.

Correspondence to Masanori Aikawa, MD, PhD, Center for Excellence in Vascular Biology, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail maikawa{at}rics.bwh.harvard.edu

Objective— Macrophage activation contributes importantly to the pathogenesis of inflammatory diseases including atherosclerosis. Macrophages exist chronically under moderate hypoxia (2% to 5% O₂) in inflamed tissues such as atherosclerotic plaques. However, macrophage phenotypes in such environments remain incompletely understood. This study tested the hypothesis that chronic moderate hypoxia induces macrophage activation and explored the underlying mechanisms.

Methods and Results— We cultured primary human macrophages derived from peripheral blood monocytes in moderate hypoxia (2% O₂ tension) or normoxia (21% O₂) for 10 days. Moderate hypoxia did not affect macrophage differentiation assessed via expression levels of scavenger receptor A. Chronic moderate hypoxia, but not normoxia, activated Akt and inactivated GSK-3β, a negative effector of Akt, thus allowing nuclear translocation of β-catenin. 2% O₂ tension increased accumulation of hypoxia-inducible factors 1 (HIF-1) transiently at 3 to 5 days. Hypoxia induced mRNA expression of the β-catenin-associated genes: MMP-7, CD44, and c-Myc. RNAi of TCF7L2, a cofactor of β-catenin, suppressed MMP-7 expression induced by hypoxia. Inhibition of Akt phosphorylation with LY294002 abolished hypoxia-induced GSK-3β inactivation, β-catenin activation, and MMP-7 expression. Macrophages under hypoxia were more resistant for oxLDL-induced apoptosis. Moreover, phospho-Akt colocalized with MMP-7 and CD44 expression in macrophages of human atherosclerotic plaques.

Conclusions— Chronic moderate hypoxia induces macrophage activation via the Akt and β-catenin pathways, providing new insight into the pathogenesis of inflammatory diseases.

Macrophages exist chronically under moderate hypoxia in atheromata. Chronic moderate hypoxia (2% O₂ tension), but not normoxia (21% O₂), activated Akt and promoted expression of the β-catenin–associated genes: MMP-7, CD44, and c-Myc. The data provide new insight into the mechanism of macrophage activation and chronic inflammation.

Key Words: macrophages • hypoxia • inflammation • atherosclerosis • MMP