166 - 23-Hydroxy Ursolic Acid Protects Atherosclerosis-prone Mice from Monocyte Dysfunction

Abstract

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 UA’s naturally occurring analogs, we identified and synthesized a compound, 23-hydroxy ursolic acid (23-OHUA), with a structural feature that we predicted to enhance both bioavailability and the protective effects of UA against monocyte dysfunction in vitro and in dyslipidemia atherosclerosis-prone mice. 23-OHUA protected monocytes from metabolic priming and dysfunction with a similar efficacy 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-sensitive to chemokines as early as 6 weeks after initiating HFD-feeding as shown by our in vivo chemotaxis assay. After 20 weeks, mice fed 23-OHUA showed 11% less weight gain compared to HFD-fed control mice and 40% reduced atherosclerotic plaque formation. Both dietary UA and 23-OHUA reduced metabolic priming and prevented the decrease in MKP-1 activity, suggesting that both compounds 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 dietary supplements for the prevention of chronic inflammatory diseases associated with metabolic disorders.