Apolipoprotein A-I and the molecular variant apoA-IMilano: Evaluation of the antiatherogenic effects in knock-in mouse model

Parolini, Cinzia; Chiesa, Giulia; Gong, Enhao; Caligari, Silvia; Cortese, Miriam M.; Koga, Tetsufumi; Forte, Trudy M.; Rubin, Edward M.

doi:10.1016/j.atherosclerosis.2005.03.008

Cited by 42 publications

(27 citation statements)

References 26 publications

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“…Recombinant HDL (ApoA-I Milano) or reconstituted HDL particle infusion causes significant reduction in aortic cholesterol content and plaque size in small clinical trials and in rabbits (36)(37)(38)(39)(40)(41). Raising the level of ApoA-I also results in a quick and significant plaque regression in mice (42)(43)(44). Consequently, approaches aimed at turning on endogenous production of ApoA-I are becoming critical strategies for increasing the number of circulating HDL particles and thus improving HDL functionality (13, 15, 45).…”

Section: Discussionmentioning

confidence: 99%

Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production

Guo¹,

Fan²,

Zhang³

et al. 2015

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production

Guo¹,

Fan²,

Zhang³

et al. 2015

Journal of Clinical Investigation

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“…40 One proposed mechanism for the increased antiatherogenic properties of apoA-I Milano is its ability to stimulate greater cholesterol efflux from peripheral macrophages, thereby increasing reverse cholesterol transport. We therefore determined the efflux potential of serum obtained from apoA-I Ϫ/Ϫ mice which were infected to express either human apoA-I or apoA-I Milano .…”

Section: The Effect Of Apoa-i and Apoa-i Milano On Cholesterol Effluxmentioning

confidence: 99%

Wild-Type ApoA-I and the Milano Variant Have Similar Abilities to Stimulate Cellular Lipid Mobilization and Efflux

Weibel

Alexander

Joshi

et al. 2007

ATVB

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Objective-The present study is a comparative investigation of cellular lipid mobilization and efflux to lipid-free human apoA-I and apoA-I Milano , reconstituted high-density lipoprotein (rHDL) particles containing these proteins and serum isolated from mice expressing human apoA-I or apoA-I Milano . Methods and Results-Cholesterol and phospholipid efflux to these acceptors was measured in cell systems designed to assess the contributions of ATP-binding cassette A1 (ABCA1), scavenger receptor type BI (SRBI), and cellular lipid content to cholesterol and phospholipid efflux. Acceptors containing the Milano variant of apoA-I showed no functional increase in lipid efflux in all assays when compared with wild-type apoA-I. In fact, in some systems, acceptors containing the Milano variant of apoA-I promoted significantly less efflux than the acceptors containing wild-type apoA-I (apoA-I wt ). Additionally, intracellular cholesteryl ester hydrolysis in macrophage foam cells was not different in the presence of either apoA-I Milano or apoA-I wt . Conclusion-Collectively these studies suggest that if the Milano variant of apoA-I offers greater atheroprotection than wild-type apoA-I, it is not attributable to greater cellular lipid mobilization.

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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

show abstract

Apolipoprotein A-I and the molecular variant apoA-IMilano: Evaluation of the antiatherogenic effects in knock-in mouse model

Cited by 42 publications

References 26 publications

Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production

Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production

Wild-Type ApoA-I and the Milano Variant Have Similar Abilities to Stimulate Cellular Lipid Mobilization and Efflux

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

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