Premium
23‐Hydroxy Ursolic Acid Protects Atherosclerosis‐Prone Mice From Monocyte Dysfunction
Author(s) -
Nguyen Huynh Nga,
Short Johnny,
Asmis Reto
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.973.13
Subject(s) - monocyte , ursolic acid , chemokine , chemistry , pharmacology , medicine , inflammation , endocrinology , immunology , chromatography
We showed that ursolic acid (UA), a pentacyclic triterpenoid with anti‐inflammatory properties, reduces atherosclerotic lesion size and improves kidney function in diabetic mice. We proposed that the atheroprotective effects of UA are due to its ability to protect monocytes against metabolic stress‐induced dysfunction or “priming”, i.e. the hyper‐responsiveness to chemokine‐induced cell adhesion and migration. Based on structure‐function analyses of nine of UA's naturally occurring structural analogs, we identified and synthesized a compound with a structural feature that we predicted to enhance both bioavailability and the protective effects of UA against monocyte dysfunction both in vitro and in dyslipidemic atherosclerosis‐prone mice. This UA analogue, 23‐hydroxy ursolic acid (23‐OHUA), protected THP‐1 monocytes and human blood monocytes from metabolic priming with a similar potency to UA. Both phytochemicals protected monocytes from metabolic stress by preventing the degradation of MAPK phosphatase‐1 (MKP‐1), a master regulator of monocyte chemotaxis and macrophage function. To test the efficacy of 23‐OHUA in protecting mice against monocyte dysfunction and atherogenesis, we fed atherosclerosis‐prone LDLR −/− mice a high fat diet (HFD) or a HFD supplemented with either 0.05% UA or 0.05% 23‐OHUA. Monocytes were primed and hyper‐reactive to chemokines as early as 6 weeks after initiating HFD‐feeding as shown by our in vivo chemotaxis assay. HFD‐fed mice also exhibit an increase in the pro‐atherogenic Ly6C hi subset. Both dietary UA and 23‐OHUA significantly reduced monocyte priming and prevented the increase in pro‐inflammatory Ly6C hi monocytes. After 20 weeks, mice fed 23‐OHUA showed a significant inhibition in weight gain compared to HFD‐fed control mice and reduced atherosclerotic plaque formation. The anti‐obesogenic and anti‐atherogenic effects of 23‐OHUA was more pronounced than those of UA. Both compounds appear to exert their anti‐inflammatory, anti‐obesogenic and anti‐atherogenic effects through a novel but common mechanism involving the protection of blood monocytes against metabolic stress‐induced priming and dysfunction. Our results suggest 23‐OHUA and UA are viable candidates for low‐cost dietary supplements for the prevention of chronic inflammatory diseases associated with metabolic disorders. Support or Funding Information This study was supported with a grant for R.A. from NIH R01 AT006885 and HNN from NIH TL1 TR001119.