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


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.


CONCLUSIONS
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.
Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio, United States.
Sarah L
SL
Ullevig
Department of Clinical Laboratory Sciences, University of Texas Health Science Center, San Antonio, United States.
Hong Seok
HS
Kim
Department of Biochemistry, University of Texas Health Science Center, San Antonio, United States.
Huynh Nga
HN
Nguyen
Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, United States.
William S
WS
Hambright
Department of Pharmacology, University of Texas Health Science Center, San Antonio, United States.
Andrew J
AJ
Robles
Department of Radiology, University of Texas Health Science Center, San Antonio, United States.
Sina
S
Tavakoli
Department of Clinical Laboratory Sciences, University of Texas Health Science Center, San Antonio, United States ; Department of Biochemistry, University of Texas Health Science Center, San Antonio, United States ; Department of Radiology, University of Texas Health Science Center, San Antonio, United States.
Reto
R
Asmis
D000199:Actins / Q000378:metabolism; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D019587:Dietary Supplements; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D054477:Glutaredoxins / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
D000199:Actins; D018932:Chemokine CCL2; D054477:Glutaredoxins; D005978:Glutathione; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D014315:Triterpenes; D000097245:Ursolic Acid; C498910:NOX4 protein, human; C422943:Nox4 protein, mouse
Atherosclerosis; GSH, reduced glutathione; Grx, glutaredoxin; HFD, high-fat diet; HG, high d-glucose; LDL, low-density lipoprotein; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MKP-1, MAPK phosphatase-1; Monocyte; Nox4; Nox4, NADPH oxidase 4; OA, oleanolic acid; PSSG, protein–glutathione mixed disulfide; ROS, reactive oxygen species; S-glutathionylation; UA, ursolic acid; Ursolic acid