Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4

Sarah L. Ullevig, Hong Seok Kim, Huynh Nga Nguyen, William S. Hambright, Andrew J. Robles, Sina Tavakoli, Reto Asmis

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Aims: Dietary supplementation with ursolic acid (UA) prevents monocyte dysfunction in diabetic mice and protects mice against atherosclerosis and loss of renal function. The goal of this study was to determine the molecular mechanism by which UA prevents monocyte dysfunction induced by metabolic stress. Methods and results: Metabolic stress sensitizes or "primes" human THP-1 monocytes and murine peritoneal macrophages to the chemoattractant MCP-1, converting these cells into a hyper-chemotactic phenotype. UA protected THP-1 monocytes and peritoneal macrophages against metabolic priming and prevented their hyper-reactivity to MCP-1. UA blocked the metabolic stress-induced increase in global protein S-glutathionylation, a measure of cellular thiol oxidative stress, and normalized actin-. S-glutathionylation. UA also restored MAPK phosphatase-1 (MKP1) protein expression and phosphatase activity, decreased by metabolic priming, and normalized p38 MAPK activation. Neither metabolic stress nor UA supplementation altered mRNA or protein levels of glutaredoxin-1, the principal enzyme responsible for the reduction of mixed disulfides between glutathione and protein thiols in these cells. However, the induction of Nox4 by metabolic stress, required for metabolic priming, was inhibited by UA in both THP-1 monocytes and peritoneal macrophages. Conclusion: UA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds.

Original languageEnglish (US)
Pages (from-to)259-266
Number of pages8
JournalRedox Biology
Volume2
Issue number1
DOIs
StatePublished - Feb 2014

Fingerprint

Physiological Stress
Monocytes
Macrophages
Peritoneal Macrophages
Sulfhydryl Compounds
Actins
Dual Specificity Phosphatase 1
Glutaredoxins
ursolic acid
Protein Phosphatase 1
Proteins
Oxidative stress
Glutathione Disulfide
Protein S
Chemotactic Factors
p38 Mitogen-Activated Protein Kinases
Dietary Supplements
Phosphoric Monoester Hydrolases
Disulfides
Oxidation-Reduction

Keywords

  • Atherosclerosis
  • Monocyte
  • Nox4
  • S-glutathionylation
  • Ursolic acid

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry

Cite this

Ullevig, S. L., Kim, H. S., Nguyen, H. N., Hambright, W. S., Robles, A. J., Tavakoli, S., & Asmis, R. (2014). Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4. Redox Biology, 2(1), 259-266. https://doi.org/10.1016/j.redox.2014.01.003

Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4. / Ullevig, Sarah L.; Kim, Hong Seok; Nguyen, Huynh Nga; Hambright, William S.; Robles, Andrew J.; Tavakoli, Sina; Asmis, Reto.

In: Redox Biology, Vol. 2, No. 1, 02.2014, p. 259-266.

Research output: Contribution to journalArticle

Ullevig, SL, Kim, HS, Nguyen, HN, Hambright, WS, Robles, AJ, Tavakoli, S & Asmis, R 2014, 'Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4', Redox Biology, vol. 2, no. 1, pp. 259-266. https://doi.org/10.1016/j.redox.2014.01.003
Ullevig, Sarah L. ; Kim, Hong Seok ; Nguyen, Huynh Nga ; Hambright, William S. ; Robles, Andrew J. ; Tavakoli, Sina ; Asmis, Reto. / Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4. In: Redox Biology. 2014 ; Vol. 2, No. 1. pp. 259-266.
@article{abb96ffb39e74ed0941250425052f919,
title = "Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4",
abstract = "Aims: Dietary supplementation with ursolic acid (UA) prevents monocyte dysfunction in diabetic mice and protects mice against atherosclerosis and loss of renal function. The goal of this study was to determine the molecular mechanism by which UA prevents monocyte dysfunction induced by metabolic stress. Methods and results: Metabolic stress sensitizes or {"}primes{"} human THP-1 monocytes and murine peritoneal macrophages to the chemoattractant MCP-1, converting these cells into a hyper-chemotactic phenotype. UA protected THP-1 monocytes and peritoneal macrophages against metabolic priming and prevented their hyper-reactivity to MCP-1. UA blocked the metabolic stress-induced increase in global protein S-glutathionylation, a measure of cellular thiol oxidative stress, and normalized actin-. S-glutathionylation. UA also restored MAPK phosphatase-1 (MKP1) protein expression and phosphatase activity, decreased by metabolic priming, and normalized p38 MAPK activation. Neither metabolic stress nor UA supplementation altered mRNA or protein levels of glutaredoxin-1, the principal enzyme responsible for the reduction of mixed disulfides between glutathione and protein thiols in these cells. However, the induction of Nox4 by metabolic stress, required for metabolic priming, was inhibited by UA in both THP-1 monocytes and peritoneal macrophages. Conclusion: UA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds.",
keywords = "Atherosclerosis, Monocyte, Nox4, S-glutathionylation, Ursolic acid",
author = "Ullevig, {Sarah L.} and Kim, {Hong Seok} and Nguyen, {Huynh Nga} and Hambright, {William S.} and Robles, {Andrew J.} and Sina Tavakoli and Reto Asmis",
year = "2014",
month = "2",
doi = "10.1016/j.redox.2014.01.003",
language = "English (US)",
volume = "2",
pages = "259--266",
journal = "Redox Biology",
issn = "2213-2317",
publisher = "Elsevier BV",
number = "1",

}

TY - JOUR

T1 - Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4

AU - Ullevig, Sarah L.

AU - Kim, Hong Seok

AU - Nguyen, Huynh Nga

AU - Hambright, William S.

AU - Robles, Andrew J.

AU - Tavakoli, Sina

AU - Asmis, Reto

PY - 2014/2

Y1 - 2014/2

N2 - Aims: Dietary supplementation with ursolic acid (UA) prevents monocyte dysfunction in diabetic mice and protects mice against atherosclerosis and loss of renal function. The goal of this study was to determine the molecular mechanism by which UA prevents monocyte dysfunction induced by metabolic stress. Methods and results: Metabolic stress sensitizes or "primes" human THP-1 monocytes and murine peritoneal macrophages to the chemoattractant MCP-1, converting these cells into a hyper-chemotactic phenotype. UA protected THP-1 monocytes and peritoneal macrophages against metabolic priming and prevented their hyper-reactivity to MCP-1. UA blocked the metabolic stress-induced increase in global protein S-glutathionylation, a measure of cellular thiol oxidative stress, and normalized actin-. S-glutathionylation. UA also restored MAPK phosphatase-1 (MKP1) protein expression and phosphatase activity, decreased by metabolic priming, and normalized p38 MAPK activation. Neither metabolic stress nor UA supplementation altered mRNA or protein levels of glutaredoxin-1, the principal enzyme responsible for the reduction of mixed disulfides between glutathione and protein thiols in these cells. However, the induction of Nox4 by metabolic stress, required for metabolic priming, was inhibited by UA in both THP-1 monocytes and peritoneal macrophages. Conclusion: UA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds.

AB - Aims: Dietary supplementation with ursolic acid (UA) prevents monocyte dysfunction in diabetic mice and protects mice against atherosclerosis and loss of renal function. The goal of this study was to determine the molecular mechanism by which UA prevents monocyte dysfunction induced by metabolic stress. Methods and results: Metabolic stress sensitizes or "primes" human THP-1 monocytes and murine peritoneal macrophages to the chemoattractant MCP-1, converting these cells into a hyper-chemotactic phenotype. UA protected THP-1 monocytes and peritoneal macrophages against metabolic priming and prevented their hyper-reactivity to MCP-1. UA blocked the metabolic stress-induced increase in global protein S-glutathionylation, a measure of cellular thiol oxidative stress, and normalized actin-. S-glutathionylation. UA also restored MAPK phosphatase-1 (MKP1) protein expression and phosphatase activity, decreased by metabolic priming, and normalized p38 MAPK activation. Neither metabolic stress nor UA supplementation altered mRNA or protein levels of glutaredoxin-1, the principal enzyme responsible for the reduction of mixed disulfides between glutathione and protein thiols in these cells. However, the induction of Nox4 by metabolic stress, required for metabolic priming, was inhibited by UA in both THP-1 monocytes and peritoneal macrophages. Conclusion: UA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds.

KW - Atherosclerosis

KW - Monocyte

KW - Nox4

KW - S-glutathionylation

KW - Ursolic acid

UR - http://www.scopus.com/inward/record.url?scp=84893349130&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893349130&partnerID=8YFLogxK

U2 - 10.1016/j.redox.2014.01.003

DO - 10.1016/j.redox.2014.01.003

M3 - Article

C2 - 24494201

AN - SCOPUS:84893349130

VL - 2

SP - 259

EP - 266

JO - Redox Biology

JF - Redox Biology

SN - 2213-2317

IS - 1

ER -