Substitution of the carboxyl-terminal domain of apo AI with apo AII sequences restores the potential of HDL to reduce the progression of atherosclerosis in apo E knockout mice.

Holvoet, Paul; Danloy, Sophie; Deridder, Els; Lox, Marleen; Bernar, Hilde; Dhoest, Ann; Collen, Désiré

doi:10.1172/jci3038

Cited by 16 publications

(13 citation statements)

References 28 publications

(30 reference statements)

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“…Consistent with our previous study, 28 overexpression of human apoA-I resulted in a significant reduction of atherosclerotic plaque volume compared with apoE KO mice ( Figure 2D). Expression of the apoA-I/apoA-II chimera also resulted in a significant reduction of atherosclerosis.…”

Section: Effects Of Apoa-i Genotype On Atherosclerotic Lesion Size Ansupporting

confidence: 92%

“…Frozen sections (7 m) were prepared for morphometric and immunohistochemical analysis. The first and most proximal section to the heart was taken Ϸ100 m distal to the point at which the aorta becomes first rounded, 28 and Ϸ12 sections per heart were analyzed. Smooth muscle cells were immunostained with a monoclonal antibody against human smooth muscle ␣-actin (clone 1A4, Dako).…”

Section: Plaque Size and Compositionmentioning

confidence: 99%

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Arg123-Tyr166 Domain of Human ApoA-I Is Critical for HDL-Mediated Inhibition of Macrophage Homing and Early Atherosclerosis in Mice

Holvoet

Peeters

Lund‐Katz

et al. 2001

ATVB

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Abstract-Atherosclerosis was studied in apolipoprotein E (apoE) knockout mice expressing human apolipoprotein A-I (apoA-I) or an apoA-I/apolipoprotein A-II (apoA-II) chimera in which the Arg123-Tyr166 central domain of apoA-I was substituted with the Ser12-Ala75 segment of apoA-II. High density lipoprotein (HDL) cholesterol levels were identical in apoA-I and apoA-I/apoA-II mice, but at 4 months, plaques were 2.7-fold larger in the aortic root of the apoA-I/apoA-II mice (PϽ0.01). The macrophage-to-smooth muscle cell ratio of lesions was 2.1-fold higher in apo-I/apoA-II mice than in apoA-I mice (PϽ0.01). This was due to a 2.7-fold higher (PϽ0.001) in vivo macrophage homing in the aortic root of apoA-I/apoA-II mice. Plasma platelet-activating factor acetyl hydrolase activity was lower (PϽ0.01) in apoA-I/apoA-II mice, resulting in increased oxidative stress, as evidenced by the higher titer of antibodies against oxidized low density lipoprotein (PϽ0.01). Increased oxidative stress resulted in increased stimulation of ex vivo macrophage adhesion by apoA-I/apoA-II ␤-very low density lipoprotein and decreased inhibition of ␤-very low density lipoprotein-induced adhesion by HDL from apoA-I/apoA-II mice. The cellular cholesterol efflux capacity of HDL from apoA-I/apoA-II mice was very similar to that of apoA-I mice. Thus, the Arg123-Tyr166 central domain of apoA-I is critical for reducing oxidative stress, macrophage homing, and early atherosclerosis in apoE knockout mice independent of its role in HDL production and cholesterol efflux. Key Words: apolipoprotein A-I Ⅲ HDL Ⅲ atherosclerosis Ⅲ oxidative stress Ⅲ macrophage homing L ow plasma levels of HDL and of their major component, apoA-I, correlate with an increased risk for coronary heart disease. 1 ApoA-I, the major protein component of HDL, is an important determinant of the concentration of HDL in human blood. 2 Expression of human apoA-I in transgenic mice resulted in increased plasma levels of small HDL particles comparable to human HDL. 3 HDL cholesterol levels and human apoA-I levels were highly correlated, and dietary fat increased HDL levels in these mice by both increasing the transport rates and decreasing the fractional catabolic rates of HDL cholesterol ester and apoA-I. 3-6 Expression of human apoA-I in the atherosclerosis-susceptible C57BL/6J mouse strain resulted in a 7-fold reduction of lesion areas in the aorta. 7 Introduction of the human apoA-I transgene in apoE knockout (KO) mice, characterized by very high levels of atherogenic ␤-VLDL and accelerated progression of complex atherosclerotic lesions, 8 -11 resulted in a significant protection against atherosclerosis. 12,13 Compared with control mice, transgenic mice expressing mouse apoA-II had increased HDL cholesterol levels but, nevertheless, exhibited increased atherosclerotic lesion development. 14 The concentration of HDL cholesterol in transgenic mice expressing human apoA-II was lower than that in control mice, probably because of the production of small HDL particles that are cleared more...

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Section: Effects Of Apoa-i Genotype On Atherosclerotic Lesion Size Ansupporting

confidence: 92%

Section: Plaque Size and Compositionmentioning

confidence: 99%

Arg123-Tyr166 Domain of Human ApoA-I Is Critical for HDL-Mediated Inhibition of Macrophage Homing and Early Atherosclerosis in Mice

Holvoet

Peeters

Lund‐Katz

et al. 2001

ATVB

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“…Two class Y helices are localized to the C terminus (aa 209 -241) and are predicted to be important components for the interaction of apoA-I with lipids (8,32). This is supported by the enhanced clearance of various apoA-I C-terminal truncation mutants when injected as lipid-free apoA-I into mice (33) or rabbits (34). Whereas it has been suggested by Mishra et al (8) that all helical domains of apoA-I contribute to lipid binding, their data indicate that the central region of the protein exhibits a much weaker affinity for lipids than the C-terminal domain (aa 209 -241).…”

Section: Discussionmentioning

confidence: 99%

Distinct Central Amphipathic α-Helices in Apolipoprotein A-I Contribute to the in Vivo Maturation of High Density Lipoprotein by Either Activating Lecithin-Cholesterol Acyltransferase or Binding Lipids

McManus¹,

Scott²,

Frank³

et al. 2000

Journal of Biological Chemistry

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Recombinant adenoviruses with cDNAs for human apolipoprotein A-I (wild type (wt) apoA-I) and three mutants, referred to as ⌬4-5A-I, ⌬5-6A-I, and ⌬6-7A-I, that have deletions removing regions coding for amino acids 100 -143, 122-165, and 144 -186, respectively, were created to study structure/function relationships of apoA-I in vivo. All mutants were expressed at lower concentrations than wt apoA-I in plasma of fasting apoA-I-deficient mice. The ⌬5-6A-I mutant was found primarily in the lipid-poor high density lipoprotein (HDL) pool and at lower concentrations than ⌬4-5A-I and ⌬6-7A-I that formed more buoyant HDL 2/3 particles. At an elevated adenovirus dose and earlier blood sampling from fed mice, both ⌬5-6A-I and ⌬6-7A-I increased HDL-free cholesterol and phospholipid but not cholesteryl ester. In contrast, wt apoA-I and ⌬4-5A-I produced significant increases in HDL cholesteryl ester. Further analysis showed that ⌬6-7A-I and native apoA-I could bind similar amounts of phospholipid and cholesterol that were reduced slightly for ⌬5-6A-I and greatly for ⌬4-5A-I. We conclude from these findings that amino acids (aa) 100 -143, specifically helix 4 (aa 100 -121), contributes to the maturation of HDL through a role in lipid binding and that the downstream sequence (aa 144 -186) centered around helix 6 (aa 144 -165) is responsible for the activation of lecithin-cholesterol acyltransferase.

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“…25,26 All experimental procedures in mice were performed in accordance with protocols approved by the Institutional Animal Care and Research Advisory Committee.…”

Section: Generation Of Transgenic Micementioning

confidence: 99%

“…The clearance rates (Cl) and the fractional catabolic rates (FCRs) of radiolabeled apolipoproteins were determined in mice as described previously. 25,26 The endogenous production rates (PRs) of the apolipoproteins were calculated from the plasma…”

Section: In Vivo Apoai Metabolismmentioning

confidence: 99%

The Arg123-Tyr166 Central Domain of Human ApoAI Is Critical for Lecithin:Cholesterol Acyltransferase–Induced Hyperalphalipoproteinemia and HDL Remodeling in Transgenic Mice

Holvoet

Geest

Linthout

et al. 2000

ATVB

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Abstract-High density lipoprotein (HDL) metabolism and lecithin:cholesterol acyltransferase (LCAT)-induced HDL remodeling were investigated in transgenic mice expressing human apolipoprotein (apo) AI or an apoAI/apoAII chimera in which the Arg123-Tyr166 domain of apoAI was substituted with the Ser12-Ala75 domain of apoAII. Expression of apoAI and of the apoAI/apoAII chimera resulted in a respective 3.5-fold and 2.9-fold increase of HDL cholesterol.Human LCAT gene transfer into apoAI-transgenic mice resulted in a 5.1-fold increase of endogenous LCAT activity. This increase was associated with a 2.4-fold increase of the cholesterol ester-to-free cholesterol ratio of HDL, a shift from HDL 3 to HDL 2 , and a 2.4-fold increase of HDL cholesterol levels. Agarose gel electrophoresis revealed that human LCAT gene transfer into human apoAI-transgenic mice resulted in an increase of pre-␤-HDL and of pre-␣-HDL. In contrast, human LCAT gene transfer did not affect cholesterol levels and HDL distribution profile in mice expressing the apoAI/apoAII chimera. Mouse LCAT did not "see" a difference between wild-type and mutant human apoAI, whereas human LCAT did, thus localizing the species-specific interaction in the central domain of apoAI. In conclusion, the Arg123-Tyr166 central domain of apoAI is not critical for in vivo lipoprotein association. It is, however, critical for LCAT-induced hyperalphalipoproteinemia and HDL remodeling independent of the lipid-binding properties of apoAI.

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Substitution of the carboxyl-terminal domain of apo AI with apo AII sequences restores the potential of HDL to reduce the progression of atherosclerosis in apo E knockout mice.

Cited by 16 publications

References 28 publications

Arg123-Tyr166 Domain of Human ApoA-I Is Critical for HDL-Mediated Inhibition of Macrophage Homing and Early Atherosclerosis in Mice

Arg123-Tyr166 Domain of Human ApoA-I Is Critical for HDL-Mediated Inhibition of Macrophage Homing and Early Atherosclerosis in Mice

Distinct Central Amphipathic α-Helices in Apolipoprotein A-I Contribute to the in Vivo Maturation of High Density Lipoprotein by Either Activating Lecithin-Cholesterol Acyltransferase or Binding Lipids

The Arg123-Tyr166 Central Domain of Human ApoAI Is Critical for Lecithin:Cholesterol Acyltransferase–Induced Hyperalphalipoproteinemia and HDL Remodeling in Transgenic Mice

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