Thiol oxidative stress induced by metabolic disorders amplifies macrophage chemotactic responses and accelerates atherogenesis and kidney injury in LDL receptor-deficient mice

Mu Qiao, Qingwei Zhao, Chi Fung Lee, Lisa R. Tannock, Eric J. Smart, Richard G. Lebaron, Clyde F. Phelix, Yolanda Rangel, Reto Asmis

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

BACKGROUND-: Strengthening the macrophage glutathione redox buffer reduces macrophage content and decreases the severity of atherosclerotic lesions in LDL receptor-deficient (LDLR -/-) mice, but the underlying mechanisms were not clear. This study examined the effect of metabolic stress on the thiol redox state, chemotactic activity in vivo, and the recruitment of macrophages into atherosclerotic lesions and kidneys of LDL-R -/- mice in response to mild, moderate, and severe metabolic stress. METHODS AND RESULTS-: Reduced glutathione (GSH) and glutathione disulfide (GSSG) levels in peritoneal macrophages isolated from mildly, moderately, and severe metabolically-stressed LDL-R -/- mice were measured by HPLC, and the glutathione reduction potential (E h) was calculated. Macrophage E h correlated with the macrophage content in both atherosclerotic (r 2=0.346, P=0.004) and renal lesions (r 2=0.480, P=0.001) in these mice as well as the extent of both atherosclerosis (r 2=0.414, P=0.001) and kidney injury (r 2=0.480, P=0.001). Compared to LDL-R -/- mice exposed to mild metabolic stress, macrophage recruitment into MCP-1-loaded Matrigel plugs injected into LDL-R mice increased 2.6-fold in moderately metabolically-stressed mice and 9.8-fold in severely metabolically-stressed mice. The macrophage E h was a strong predictor of macrophage chemotaxis (r 2=0.554, P<0.001). CONCLUSION-: Thiol oxidative stress enhances macrophage recruitment into vascular and renal lesions by increasing the responsiveness of macrophages to chemoattractants. This novel mechanism contributes at least in part to accelerated atherosclerosis and kidney injury associated with dyslipidemia and diabetes in mice.

Original languageEnglish (US)
Pages (from-to)1779-1786
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume29
Issue number11
DOIs
StatePublished - Nov 1 2009

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Keywords

  • Atherosclerosis
  • Glutathione
  • Inflammation
  • Macrophage recruitment
  • Metabolic stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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