Inflammatory mediators are perpetuated in macrophages resistant to apoptosis induced by hypoxia

Jong K. Yun, Thomas S. McCormick, Claudia Villabona, Raymond R. Judware, María B. Espinosa, Eduardo G. Lapetina

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42 Scopus citations

Abstract

A hypoxic/anoxic microenvironment has been proposed to exist within a vascular lesion due to intimal or medial cell proliferation in vascular diseases. Here, we examined whether hypoxia alters macrophage function by exposing murine macrophage-like RAW 264.7 (RAW) cells to hypoxia (2% O2). When cells were exposed to hypoxia, a significant number of RAW cells underwent apoptosis. Additionally, small subpopulations of RAW cells were resistant to hypoxia-induced apoptosis. Through repeated cycles of hypoxia exposure, hypoxia-induced apoptosis-resistant macrophages (HARMs) were selected; HARM cells demonstrate >70% resistance to hypoxia-induced apoptosis, as compared with the parental RAW cells. When heat shock protein (HSP) expression was examined after hypoxia, we observed a significant decrease in constitutive heat shock protein 70 (HSC 70) in RAW cells, but not in HARMs, as compared with the control normoxic condition (21% O2). In contrast, the expression level of glucose-regulated protein 78 (GRIP 78) in RAW and HARM cells after hypoxia treatment was not altered, suggesting that HSC 70 and not GRP 78 my play a role in protection against hypoxia-induced apoptosis. When tumor necrosis factor a (TNF-α) production was examined after hypoxic treatment, a significant increase in TNF-α production in HARM but decrease in RAW was observed, as compared with cells cultured in normoxic conditions. HARM cells also exhibit a much lower level of modified-LDL uptake than do RAW cells, suggesting that HARMs may not transform into foam cells. These results suggest that a selective population of macrophages may adapt to potentially pathological hypoxic conditions by overcoming the apoptotic signal.

Original languageEnglish (US)
Pages (from-to)13903-13908
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number25
DOIs
StatePublished - Dec 9 1997

All Science Journal Classification (ASJC) codes

  • General

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