Recombinant HDL(Milano) exerts greater anti-inflammatory and plaque stabilizing properties than HDL(wild-type).
OBJECTIVE
The aim of this study was to compare the effects of HDL(Milano) and HDL(wild-type), on regression and stabilization of atherosclerosis.


METHODS
Atherosclerotic New Zealand White rabbits received 2 infusions, 4 days apart, of HDL(Milano) (75mg/kg of apoA-I(Milano)), HDL(wild-type) (75mg/kg apoA-I(wild-type)) or placebo. Pre- and post-treatment plaque volume was assessed by MRI. Markers of plaque vulnerability and inflammation were evaluated. Liver and aortic cholesterol content, aortic ABCA-1 and liver SR-BI were quantified. The effect of apoA-I Milano and wild-type proteins on MCP-1 and COX-2 expression by macrophages was evaluated in vitro.


RESULTS
Both forms of HDL induced aortic plaque regression (-4.1% and -2.6% vs. pre-treatment in HDL(Milano) and HDL(wild-type) respectively, p<0.001 and p=0.009). A similar reduction in cholesterol content of aorta and liver was observed with both treatments vs. placebo. The expression of aortic ABCA-1 and hepatic SR-BI was significantly higher in both treated groups vs. placebo. A significantly reduced plaque macrophage density was observed in the HDL(Milano) vs. both HDL(wild-type) and placebo groups. Plaque levels of COX-2, MCP-1, Caspase-3 antigen and MMP-2 activity were significantly reduced in the HDL(Milano) vs. both HDL(wild-type) and placebo groups. In vitro studies showed that apoA-I(Milano) protein significantly reduced expression of COX-2 and MCP-1 in oxLDL loaded macrophages vs. apoA-I(wild-type).


CONCLUSIONS
Despite a similar effect on acute plaque regression, the infusion of HDL(Milano) exerts superior anti-inflammatory and plaque stabilizing effects than HDL(wild-type) in the short term.
Atherothrombosis Research Unit, The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Borja
B
Ibanez
Chiara
C
Giannarelli
Giovanni
G
Cimmino
Carlos G
CG
Santos-Gallego
Matilde
M
Alique
Antonio
A
Pinero
Gemma
G
Vilahur
Valentin
V
Fuster
Lina
L
Badimon
Juan J
JJ
Badimon
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D000975:Antioxidants / Q000008:administration & dosage; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016632:Apolipoprotein A-I / Q000008:administration & dosage*; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D018955:CD36 Antigens / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D007262:Infusions, Intravenous; D015227:Lipid Peroxidation / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000008:administration & dosage*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010713:Phosphatidylcholines / Q000008:administration & dosage*; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage; D013997:Time Factors
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016632:Apolipoprotein A-I; C111835:CCL2 protein, human; D018955:CD36 Antigens; D018932:Chemokine CCL2; C474616:ETC216; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010713:Phosphatidylcholines; D011994:Recombinant Proteins; C080631:apolipoprotein A-I Milano; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2