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

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

Research output: Contribution to journalArticle

41 Citations (Scopus)

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

Fingerprint

Macrophages
Apoptosis
Cell Hypoxia
HSP70 Heat-Shock Proteins
Hypoxia
Tumor Necrosis Factor-alpha
Tunica Intima
Foam Cells
Heat-Shock Proteins
Vascular Diseases
Blood Vessels
Cultured Cells
Cell Count
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • General

Cite this

Yun, Jong ; McCormick, Thomas S. ; Villabona, Claudia ; Judware, Raymond R. ; Espinosa, María B. ; Lapetina, Eduardo G. / Inflammatory mediators are perpetuated in macrophages resistant to apoptosis induced by hypoxia. In: Proceedings of the National Academy of Sciences of the United States of America. 1997 ; Vol. 94, No. 25. pp. 13903-13908.
@article{a8c2968743524c6299aee546a5089d76,
title = "Inflammatory mediators are perpetuated in macrophages resistant to apoptosis induced by hypoxia",
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.",
author = "Jong Yun and McCormick, {Thomas S.} and Claudia Villabona and Judware, {Raymond R.} and Espinosa, {Mar{\'i}a B.} and Lapetina, {Eduardo G.}",
year = "1997",
month = "12",
day = "9",
doi = "10.1073/pnas.94.25.13903",
language = "English (US)",
volume = "94",
pages = "13903--13908",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "25",

}

Inflammatory mediators are perpetuated in macrophages resistant to apoptosis induced by hypoxia. / Yun, Jong; McCormick, Thomas S.; Villabona, Claudia; Judware, Raymond R.; Espinosa, María B.; Lapetina, Eduardo G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 25, 09.12.1997, p. 13903-13908.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inflammatory mediators are perpetuated in macrophages resistant to apoptosis induced by hypoxia

AU - Yun, Jong

AU - McCormick, Thomas S.

AU - Villabona, Claudia

AU - Judware, Raymond R.

AU - Espinosa, María B.

AU - Lapetina, Eduardo G.

PY - 1997/12/9

Y1 - 1997/12/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0031457558&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031457558&partnerID=8YFLogxK

U2 - 10.1073/pnas.94.25.13903

DO - 10.1073/pnas.94.25.13903

M3 - Article

C2 - 9391125

AN - SCOPUS:0031457558

VL - 94

SP - 13903

EP - 13908

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 25

ER -