Abstracts from a PubMed search on "Apo A-I Milano"
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Biophys J 2000 Sep;79(3):1679-85 Related Articles, Books, LinkOut
Molecular belt models for the apolipoprotein A-I Paris and Milano mutations.
Klon AE, Jones MK, Segrest JP, Harvey SC.
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
Models for the binding of the 200-residue carboxy-terminal domain of two mutants of apolipoprotein A-I (apo A-I), apo A-I(R173C)(Milano) and apo A-I(R151C)(Paris), to lipid in discoidal high-density lipoprotein (HDL) particles are presented. In both models, two monomers of the mutant apo A-I molecule bind to lipid in an antiparallel manner, with the long axes of their helical repeats running perpendicular to the normal of the lipid bilayer to form a single disulfide-linked homodimer. The overall structures of the models of these two mutants are very similar, differing only in helix-helix registration. Thus these models are consistent with experimental observations that reconstituted HDL particles containing apo A-I(Milano) and apo A-I(Paris) are very similar in diameter to reconstituted HDL particles containing wild-type apo A-I, and they support the belief that apo A-I binds to lipid in discoidal HDL particles via the belt conformation.
PMID: 10969027 [PubMed - indexed for MEDLINE]
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: Circulation 1998 Mar 3;97(8):780-5
Effects of recombinant apolipoprotein A-I(Milano) on aortic atherosclerosis in apolipoprotein E-deficient mice.
Shah PK, Nilsson J, Kaul S, Fishbein MC, Ageland H, Hamsten A, Johansson J, Karpe F, Cercek B.
Atherosclerosis Research Center, Division of Cardiology, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif 90048, USA. shahp@csmc.edu
BACKGROUND: We previously reported marked inhibitory effects of recombinant apolipoprotein (apo) A-I(Milano)/phospholipid complex (A-I[Milano]/PC) on neointimal lesions in balloon-injured iliofemoral arteries of hypercholesterolemic rabbits. In this study, we tested the hypothesis that apo A-I(Milano)/PC would inhibit aortic atherosclerosis in apo E-deficient mice. METHODS AND RESULTS: Thirty-five apo E-deficient mice fed a high-cholesterol diet were included in the study. Control mice were killed at 20 (n=8) or 25 (n=7) weeks. Treated mice received 18 injections of either 40 mg/kg apo A-I(Milano)/PC (n=15) or PC only (n=5) intravenously every other day from 20 weeks until death at 25 weeks. Aortic atherosclerosis was identified with Sudan IV staining. Lipid and macrophage contents of the aortic sinus plaques were measured after oil-red O and Mac-1 antibody staining, respectively, and quantified with computed morphometry. In control mice, from 20 to 25 weeks, aortic atherosclerosis increased by 59% (11 +/- 1% versus 17 +/- 5% of the aortic surface, P=.002), and lipid content increased by 45% (22 +/- 8% versus 32 +/- 6% of plaque area, P=.02) without a significant change in macrophage content (10.8 +/- 2% versus 13.2 +/- 6%). Compared with 20-week-old untreated control mice, PC only-treated mice at 25 weeks demonstrated a 32% increase in aortic atherosclerosis (11 +/- 1% versus 15 +/- 4%, P=.01) and an increase in lipid content (22 +/- 8% versus 47 +/- 3%, P<.0001) without a change in macrophage content (10.8 +/- 2% versus 11 +/- 2%). In comparison with 20-week-old untreated control mice, 25-week-old apo A-I(Milano)/PC-treated mice demonstrated no increase in aortic atherosclerosis (11 +/- 1% versus 10 +/- 4%, P=NS), a 40% reduction in lipid content (22 +/- 8% versus 13 +/- 8%, P=.01), and a 46% reduction in macrophage content (10.8 +/- 2% versus 5.8 +/- 2.9%; P=.03). Serum cholesterol levels were markedly elevated in all groups and did not change significantly with apo A-I(Milano)/PC or PC only. In vitro, apo A-I(Milano)/PC stimulated cholesterol efflux from cholesterol-loaded FU5AH hepatoma cell lines in a dose-dependent manner, whereas PC only or PC-free apo A-I(Miano) had no effect. CONCLUSIONS: Recombinant A-I(Milano)/PC prevented progression of aortic atherosclerosis and reduced lipid and macrophage content of plaques in apo E-deficient mice despite severe hypercholesterolemia. Thus, A-I(Milano)/PC may have a role in inhibiting progression and promoting stabilization of atherosclerosis.
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Atherosclerosis 1999 Jan;142(1):29-40
Recombinant apolipoproteins for the treatment of vascular diseases.
Sirtori CR, Calabresi L, Franceschini G.
Center E. Grossi Paoletti, Institute of Pharmacological Sciences, University of Milano, Italy.
The protein components of human lipoproteins, apolipoproteins, allow the redistribution of cholesterol from the arterial wall to other tissues and exert beneficial effects on systems involved in the development of arterial lesions, like inflammation and hemostasis. Because of these properties, the antiatherogenic apolipoproteins, particularly apo A-I and apo E, may provide an innovative approach to the management of vascular diseases. The recent availability of extractive or biosynthetic molecules is allowing a detailed overview of their therapeutic potential in a number of animal models of arterial disease. Infusions of apo E, or more dramatically, of apo A-I, both recombinant or extractive, cause a direct reduction of the atherosclerotic burden in experimental animals. Naturally, as the apo A-I(Milano) (apo A-I(M)) dimer, or engineered recombinant apolipoproteins with prolonged permanence in plasma and improved function may offer an even better approach to the therapeutic handling of arterial disease. This progress will go on in parallel with innovations in the technologies for direct, non invasive assessments of human atherosclerosis, thus allowing closer monitoring of this potential new approach to therapy.
Publication Types:
Review
Review, academic
PMID: 9920503 [PubMed - indexed for MEDLINE]
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Circulation 1994 Oct;90(4):1935-41
Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits.
Ameli S, Hultgardh-Nilsson A, Cercek B, Shah PK, Forrester JS, Ageland H, Nilsson J.
Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
BACKGROUND: Several epidemiological studies have shown an inverse relation between high-density lipoprotein (HDL) cholesterol levels and coronary heart disease. Recently, observational studies have suggested a similar inverse relation between HDL and restenosis after coronary balloon angioplasty. Despite these observations, it is unclear whether this inverse relation reflects a direct vascular protective effect of HDL or apolipoprotein (apo) A-I, the major apolipoprotein component of HDL. Therefore, to determine whether HDL directly influences neointima formation, we investigated the effect of recombinant apo A-I Milano (apo A-I M), a mutant of human apo A-I with Arg-173 to Cys substitution, on intimal thickening after balloon injury in cholesterol-fed rabbits. METHODS AND RESULTS: Cholesterol feeding was initiated 18 days before injury and continued until the time of death. Eight rabbits received intravenous injections of 40 mg of apo A-I M linked to a phospholipid carrier on alternate days, beginning 5 days before and continuing for 5 days after balloon injury of femoral and iliac arteries. Eight rabbits received the carrier alone, and four received neither apo A-I M nor the carrier. Three weeks after balloon injury, apo A-I M-treated rabbits had significantly reduced intimal thickness compared with the two control groups (mean +/- SD): 0.49 +/- 0.29 versus 1.14 +/- 0.38 mm2 and 1.69 +/- 0.43 mm2, P < .002 by ANOVA). The intima-to-media ratio was also significantly reduced by apo A-I M (0.7 +/- 0.2 versus 1.5 +/- 0.5 and 2.1 +/- 0.1, P < .002 by ANOVA) compared with the two controls. The fraction of intimal lesion covered by macrophages, as identified by immunohistochemistry using macrophage-specific monoclonal antibody, was significantly less in apo A-I M-treated rabbits compared with carrier-treated animals (25.3 +/- 17% versus 59.4 +/- 12.3%, P < .005). Aortic cholesterol content, measured in an additional 10 rabbits, did not differ significantly between apo A-I M-treated animals (n = 5) and carrier-treated controls (n = 5). CONCLUSIONS: Apo A-I M significantly reduced intimal thickening and macrophage content after balloon injury in cholesterol-fed rabbits without a change in arterial total cholesterol content. Although the precise mechanism of action remains to be defined, these findings are consistent with a direct vascular effect of apo A-I, which could have potential therapeutic implications.
PMID: 7923682 [PubMed - indexed for MEDLINE]
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Arteriosclerosis 1984 Jul-Aug;4(4):303-22
Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency.
Schaefer EJ.
This review assesses current knowledge of the clinical, genetic, and biochemical features of familial high density lipoprotein (HDL) deficiency syndromes. The focus is on HDL deficiency states occurring in the absence of severe hypertriglyceridemia or lecithin/cholesterol acyltransferase deficiency. Specific entities falling within this category include Tangier disease, familial HDL deficiency with planar xanthomas, familial apolipoprotein A-I and C-III deficiency (formerly known as apolipoprotein A-I absence), familial deficiency of apolipoprotein A-I and C-III, fish-eye disease, familial hypoalphalipoproteinemia, and apolipoprotein A-I variants (apo A-I Milano, apo A-I Marburg, apo A-I Giessen, and apo A-I Munster 1-3). Diffuse corneal opacification and premature coronary artery disease are common features in many of these kindreds. No striking clinical abnormalities have been noted in patients with currently known apolipoprotein A-I variants, possibly because these subjects are heterozygotes for their respective defects. The HDL deficiency in many of these disorders has been associated with abnormalities or deficiencies of apolipoprotein A-I. Further research will undoubtedly define the defects in all the disorders that have been described, uncover new mutations, as well as provide additional insights into the precise relationship between HDL deficiency and atherosclerosis.
Publication Types:
Review
PMID: 6431953 [PubMed - indexed for MEDLINE]
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