Increased Cholesterol Efflux Potential of Sera From ApoA-I
            <sub>Milano</sub>
            Carriers and Transgenic Mice

Franceschini, Guido; Calabresi, Laura; Chiesa, Giulia; Parolini, Cinzia; Sirtori, Cesare R.; Canavesi, M.; Bernini, Franco

doi:10.1161/01.atv.19.5.1257

Cited by 115 publications

(71 citation statements)

References 39 publications

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“…32 This may certainly contribute to the apparently improved capacity for cell cholesterol removal, as shown in a variety of in vitro and ex vivo experiments. 14,33 Several antiatherosclerotic properties have been attributed to HDL and apoA-I. 34 Very recently, Spieker et al 35 reported clinical findings indicative of a restored endothelial function in hypercholesterolemic patients after infusion with reconstituted HDL.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Apolipoprotein A-I _Milano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks

Chiesa

Monteggia

Marchesi

et al. 2002

Circulation Research

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195

104

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Abstract-Apolipoprotein A-I Milano (AIM), a natural variant of human apolipoprotein A-I, confers to carriers a significant protection against vascular disease. In previous studies, administration of recombinant AIM-phospholipid (AIM-PL) complexes to hypercholesterolemic rabbits markedly inhibited neointimal formation after arterial injury; moreover, repeated injections of AIM-PL in apoE-deficient mice significantly reduced atherosclerosis progression. The objective of the present study was to determine if a single localized infusion of AIM-PL complexes administered directly to atheromatous lesions could promote plaque regression. Lipid-rich, atheromatous plaques were generated at both common carotid arteries of 25 rabbits by applying a perivascular electric injury, followed by 1.5% cholesterol diet for 90 days. Rabbits were infused with either saline, phospholipid vesicles, or 3 different AIM-PL doses (250, 500, or 1000 mg of protein) delivered through an intravascular ultrasound (IVUS) catheter positioned at the origin of the right carotid. The lesions at the left carotid artery were therefore exposed to the agents systemically. Infusion of AIM-PL at the 2 highest doses caused reduction of right carotid artery plaque area by the end a 90-minute infusion as assessed by IVUS analysis. Plaque area regression was confirmed by histology in carotid arteries receiving direct (500 and 1000 mg doses) and systemic (500 mg dose) delivery, 72 hours after the start of the treatment. Plaque lipid content was associated with significant and similar decreases in Oil Red O staining in both arteries. These results suggest AIM-PL complexes enhanced lipid removal from arteries is the mechanism responsible for the observed plaque changes.

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Section: Discussionmentioning

confidence: 99%

Recombinant Apolipoprotein A-I _Milano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks

Chiesa

Monteggia

Marchesi

et al. 2002

Circulation Research

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195

104

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“…3 Studies in human carriers and transgenic mice expressing the apoA-I M mutant disclosed a high capacity of serum to extract cholesterol from peripheral cells, 27 consequent to the peculiar structural and functional properties of the mutant. Indeed, earlier studies have shown that monomeric apoA-I M has a higher affinity for lipids 28 and a faster catabolism than the wild-type apoA-I.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Status of Carriers of the Apolipoprotein A-I _Milano Mutant

et al. 2001

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Background-Carriers of the apolipoprotein A-I Milano (apoA-I M ) mutant present with very low plasma HDL cholesterol and moderate hypertriglyceridemia, apparently not leading to premature coronary heart disease. The objective of this study was to establish whether this high-risk lipid/lipoprotein profile is associated with structural changes in the carotid arteries and heart, indicative of preclinical atherosclerosis. Methods and Results-Twenty-one A-I M carriers were compared with age-and sex-matched control subjects from the same kindred and with 2 series of matched subjects with primary hypoalphalipoproteinemia (HA). Structural changes in the carotid arteries were defined as the intima-media thickness (IMT) measured by B-mode ultrasound. HA subjects, both recruited among patients attending our Lipid Clinic and blood donors, showed significant thickening of the carotids (average IMT, 0.86Ϯ0.25 and 0.88Ϯ0.29 mm, respectively) compared with control subjects (average IMT, 0.64Ϯ0.12 mm); the apoA-I M carriers instead showed normal arterial thickness (average IMT, 0.63Ϯ0.10 mm). Moreover, a significantly higher prevalence of atherosclerotic plaques was found in patients and blood donors with HA (both 57%) compared with apoA-I M carriers (33%) and control subjects (21%). Echocardiographic findings and maximal treadmill ECG did not differ significantly between apoA-I M carriers and control subjects, apart from a slight increase in left ventricular end-diastolic dimension in the carriers. Conclusions-Despite severe HA, carriers of the apoA-I M mutant do not show structural changes in the arteries and heart, in contrast to HA subjects, who are characterized by a marked increase in carotid IMT and increased prevalence of atherosclerotic plaques.

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“…Despite a lipid profile that is usually associated with a high risk of premature cardiovascular disease, apoA-I M carriers display no increase in cardiovascular disease or events (10,14,15). This has led to speculation that apoA-I M is a gainof-function mutation that has enhanced cardio-protective effects (16)(17)(18)(19)(20)(21)(22), while others believe that wild-type (WT) apoA-I and apoA-I M are functionally equivalent (23,24). A clinical trial of repeated intravenous infusions of apoA-I M -phospholipid complexes demonstrated regression of existing atheromas after five weekly treatments (25,26).…”

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confidence: 99%

Structural and functional consequences of the Milano mutation (R173C) in human apolipoprotein A-I

Alexander

Tanaka

Kono

et al. 2009

Journal of Lipid Research

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Carriers of the apolipoprotein A-I Milano (apoA-I M ) variant, R173C, have reduced levels of plasma HDL but no increase in cardiovascular disease. Despite intensive study, it is not clear whether the removal of the arginine or the introduction of the cysteine is responsible for this altered functionality. We investigated this question using two engineered variations of the apoA-I M mutation: R173S apoA-I, similar to apoA-I M but incapable of forming a disulfide bond, and R173K apoA-I, a conservative mutation. Characterization of the lipid-free proteins showed that the order of stability was wild type≈R173K.R173S.R173C. Compared with wildtype apoA-I, apoA-I M had a lower affinity for lipids, while R173S apoA-I displayed intermediate affinity. The in vivo effects of the apoA-I variants were measured by injecting apoA-I-expressing adeno-associated virus into apoA-I-null mice. Mice that expressed the R173S variant again showed an intermediate phenotype. Thus, both the loss of the arginine and its replacement by a cysteine contribute to the altered properties of apoA-I M . The arginine is potentially involved in an intrahelical salt bridge with E169 that is disrupted by the loss of the positively charged arginine and repelled by the cysteine, destabilizing the helix bundle domain in the apoA-I molecule and modifying its lipid binding

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Increased Cholesterol Efflux Potential of Sera From ApoA-I _Milano Carriers and Transgenic Mice

Abstract: Abstract-The ability of HDL to remove cholesterol from peripheral cells and drive it to the liver for excretion is believed to explain most of the strong inverse correlation between plasma HDL cholesterol levels and coronary heart disease.

Cited by 115 publications

References 39 publications

Recombinant Apolipoprotein A-I _Milano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks

Recombinant Apolipoprotein A-I _Milano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks

Cardiovascular Status of Carriers of the Apolipoprotein A-I _Milano Mutant

Structural and functional consequences of the Milano mutation (R173C) in human apolipoprotein A-I

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Increased Cholesterol Efflux Potential of Sera From ApoA-I Milano Carriers and Transgenic Mice

Abstract: Abstract-The ability of HDL to remove cholesterol from peripheral cells and drive it to the liver for excretion is believed to explain most of the strong inverse correlation between plasma HDL cholesterol levels and coronary heart disease.

Cited by 115 publications

References 39 publications

Recombinant Apolipoprotein A-I Milano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks

Recombinant Apolipoprotein A-I Milano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks

Cardiovascular Status of Carriers of the Apolipoprotein A-I Milano Mutant

Structural and functional consequences of the Milano mutation (R173C) in human apolipoprotein A-I

Contact Info

Product

Resources

About

Increased Cholesterol Efflux Potential of Sera From ApoA-I _Milano Carriers and Transgenic Mice

Recombinant Apolipoprotein A-I _Milano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks

Recombinant Apolipoprotein A-I _Milano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks

Cardiovascular Status of Carriers of the Apolipoprotein A-I _Milano Mutant