title: Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis.
abstract: OBJECTIVE
  Accelerated atherosclerosis is a major diabetic complication initiated by the enhanced recruitment of monocytes into the vasculature. In this study, we examined the therapeutic potential of the phytonutrients ursolic acid (UA) and resveratrol (RES) in preventing monocyte recruitment and accelerated atherosclerosis.
  
  
  RESULTS
  Dietary supplementation with either RES or UA (0.2%) protected against accelerated atherosclerosis induced by streptozotocin in high-fat diet-fed LDL receptor-deficient mice. However, mice that received dietary UA for 11 weeks were significantly better protected and showed a 53% reduction in lesion formation while mice fed a RES-supplemented diet showed only a 31% reduction in lesion size. Importantly, UA was also significantly more effective in preventing the appearance of proinflammatory GR-1(high) monocytes induced by these diabetic conditions and reducing monocyte recruitment into MCP-1-loaded Matrigel plugs implanted into these diabetic mice. Oxidatively stressed THP-1 monocytes mimicked the behavior of blood monocytes in diabetic mice and showed enhanced responsiveness to monocyte chemoattractant protein-1 (MCP-1) without changing MCP-1 receptor (CCR2) surface expression. Pretreatment of THP-1 monocytes with RES or UA (0.3-10μM) for 15h resulted in the dose-dependent inhibition of H(2)O(2)-accelerated chemotaxis in response to MCP-1, but with an IC(50) of 0.4μM, UA was 2.7-fold more potent than RES.
  
  
  CONCLUSIONS
  Dietary UA is a potent inhibitor of monocyte dysfunction and accelerated atherosclerosis induced by diabetes. These studies identify ursolic acid as a potential therapeutic agent for the treatment of diabetic complications, including accelerated atherosclerosis, and provide a novel mechanism for the anti-atherogenic properties of ursolic acid.
authors.affiliation: Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, United States.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Ullevig
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Zhao
authors.forename: Debora
authors.initials: D
authors.lastname: Zamora
authors.forename: Reto
authors.initials: R
authors.lastname: Asmis
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D018384:Oxidative Stress / Q000187:drug effects; D054390:Receptors, CCR2 / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013997:Time Factors; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D002317:Cardiovascular Agents; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D011973:Receptors, LDL; D000077185:Resveratrol; D013267:Stilbenes; D014315:Triterpenes; D000097245:Ursolic Acid