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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1426.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

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

Mohamad Navab; G.M. Anantharamaiah; Susan Hama; Greg Hough; Srinivasa T. Reddy; Joy S. Frank; David W. Garber; Shaila Handattu; Alan M. Fogelman

From the From the David Geffen School of Medicine at University of California, Los Angeles (M.N., S.Hama, G.H., S.T.R., J.S.F., A.M.F.), Calif; and the Department of Medicine (G.M.A., D.W.G., S. Handattu), and the Atherosclerosis Research Unit, University of Alabama at Birmingham.

Correspondence to Mohamad Navab, PhD, Room 47–123 CHS, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1679. E-mail mnavab{at}mednet.ucla.edu

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; 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.

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.

Key Words: atherosclerosis • lipoproteins • HDL • apoA-I mimetic peptides • statins

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