Effect of treatment with human apolipoprotein A-I on atherosclerosis in uremic apolipoprotein-E deficient mice.
OBJECTIVE
Uremia markedly increases the risk of atherosclerosis. Thus, effective anti-atherogenic treatments are needed for uremic patients. This study examined effects of non-lipidated recombinant human apoA-I (h-apoA-I) and a recombinant trimeric apoA-I molecule (TripA-I) on lipid metabolism and atherosclerosis in uremic apoE-/- mice.


RESULTS
Upon intraperitoneal injection, h-apoA-I and TripA-I rapidly associated with plasma HDL and reduced mouse apoA-I plasma levels without affecting total or HDL cholesterol concentrations. The plasma half-life was approximately 36 h for TripA-I and approximately 16 h for h-apoA-I. Injection of h-apoA-I (100mg/kg) or TripA-I (100mg/kg) twice weekly for 7 weeks did not affect the cross-sectional area of atherosclerotic lesions in the aortic root, or the en face lesion area and cholesterol content in the thoracic aorta in uremic apoE-/- mice. Also, the treatments did not affect expression of selected inflammatory genes in the thoracic aorta or plasma concentrations of soluble ICAM-1 and VCAM-1. However, h-apoA-I-treated mice had larger smooth muscle cell-staining areas in aortic root plaques than PBS-treated mice (4.8+/-0.8% vs. 2.5+/-0.6%, P<0.05).


CONCLUSIONS
The data suggest that long-term treatment with non-lipidated h-apoA-I or TripA-I might affect plaque composition but does not reduce atherosclerotic lesion size in uremic apoE-/- mice.
Pedersen
Tanja X
TX
Department of Clinical Biochemistry, KB 3011, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark. tanja.xenia.pedersen@rh.hosp.dk
Bro
Susanne
S
Andersen
Mikkel H
MH
Etzerodt
Michael
M
Jauhiainen
Matti
M
Moestrup
Søren
S
Nielsen
Lars B
LB
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D016632:Apolipoprotein A-I / Q000097:blood / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D053508:Matrix Metalloproteinase 12 / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000097:blood / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood; D014511:Uremia / Q000150:complications*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D011994:Recombinant Proteins; D014280:Triglycerides; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002784:Cholesterol; D019278:Matrix Metalloproteinase 3; D053508:Matrix Metalloproteinase 12