D-4F and Statins Synergize to Render HDL Antiinflammatory in Mice and Monkeys and Cause Lesion Regression in Old Apolipoprotein E–Null Mice

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Abstract
Objectives— 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; PP=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; PP=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. D-4F and pravastatin when given in combination at oral doses that were ineffective when given as single agents rendered HDL antiinflammatory in mice and monkeys and prevented atherosclerosis in young and caused regression of established lesions in old apoE null mice.

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