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


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.
Navab
Mohamad
M
Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, Calif 90095-1679, USA. mnavab@mednet.ucla.edu
Anantharamaiah
G M
GM
Hama
Susan
S
Hough
Greg
G
Reddy
Srinivasa T
ST
Frank
Joy S
JS
Garber
David W
DW
Handattu
Shaila
S
Fogelman
Alan M
AM
D000367:Age Factors; D000821:Animal Feed; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000378:metabolism / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D008076:Cholesterol, HDL / Q000276:immunology* / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000166:cytology; D017035:Pravastatin / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; C465468:D-4F peptide; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017035:Pravastatin