D-4F and statins synergize to render HDL antiinflammatory in mice and monkeys and cause lesion regression in old apolipoprotein E-null mice.

Academic Article

Abstract

  • OBJECTIVE: We tested for synergy between pravastatin and D-4F by administering oral doses of each in combination that were predetermined to be ineffective when given as single agents. METHODS AND RESULTS: The combination significantly increased high-density lipoprotein (HDL)-cholesterol levels, apolipoprotein (apo)A-I levels, paraoxonase activity, rendered HDL antiinflammatory, prevented lesion formation in young (79% reduction in en face lesion area; P<0.0001) and caused regression of established lesions in old apoE null mice (ie, mice receiving the combination for 6 months had lesion areas that were smaller than those before the start of treatment (P=0.019 for en face lesion area; P=0.004 for aortic root sinus lesion area). After 6 months of treatment with the combination, en face lesion area was 38% of that in mice maintained on chow alone; P<0.00004) with a 22% reduction in macrophage content in the remaining lesions (P=0.001), indicating an overall reduction in macrophages of 79%. The combination increased intestinal apoA-I synthesis by 60% (P=0.011). In monkeys, the combination also rendered HDL antiinflammatory. CONCLUSIONS: These results suggest that the combination of a statin and an HDL-based therapy may be a particularly potent treatment strategy.
  • Keywords

  • Age Factors, Animal Feed, Animals, Anti-Inflammatory Agents, Apolipoprotein A-I, Apolipoproteins E, Atherosclerosis, Cells, Cultured, Chemotaxis, Leukocyte, Cholesterol, HDL, Drug Synergism, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Intestinal Mucosa, Macaca fascicularis, Male, Mice, Mice, Mutant Strains, Monocytes, Pravastatin
  • Digital Object Identifier (doi)

    Author List

  • Navab M; Anantharamaiah GM; Hama S; Hough G; Reddy ST; Frank JS; Garber DW; Handattu S; Fogelman AM
  • Start Page

  • 1426
  • End Page

  • 1432
  • Volume

  • 25
  • Issue

  • 7