Apolipoprotein A-IMilano (apoA-IM) is characterized by a Cys for Arg substitution and formation of homo- and apoA-II heterodimers. In the last years, some important insights on apoA-IM have been provided, i.e. that apoA-IM/apoA-IM has a very long permanence in blood, as well as a high capacity to remove tissue cholesterol, in addition to further attractive properties. These effects stimulated a number of attempts on alternative developments in high-density lipoprotein (HDL) therapy, i.e. to the so-called apoA-I mimetics. A frequent criticism, i.e. the lack of a detailed comparative assessment of the capacity of apoA-I versus apoA-IM in arterial cholesterol removal, has recently been overcome by a trial of gene therapy with apoA-IM versus wild-type apoA-I in hyperlipidemic mice. Structural studies on the dimer indicate that this very stable compound is present in small HDL, containing a single molecule of dimer, and apparently is responsible for the higher effectiveness of apoA-IM sera in mobilizing cholesterol from macrophages, when the ATP-binding cassette, subfamily A, member 1 (ABCA1)-driven efflux is stimulated. An additional protective trait of apoA-IM carriers is the peculiar susceptibility to proteolysis of the heterodimer, an interesting hypothetical mechanism for cardiovascular protection. The heterodimer would, in fact, act as a suicide substrate for arterial metalloproteinases, responsible for plaque rupture.
ApoA-IMilano from structure to clinical application / I. Eberini, E. Gianazza, L. Calabresi, C.R. Sirtori. - In: ANNALS OF MEDICINE. - ISSN 0785-3890. - 40:Suppl. 1(2008), pp. 48-56.
ApoA-IMilano from structure to clinical application
I. EberiniPrimo
;E. GianazzaSecondo
;L. CalabresiPenultimo
;C.R. SirtoriUltimo
2008
Abstract
Apolipoprotein A-IMilano (apoA-IM) is characterized by a Cys for Arg substitution and formation of homo- and apoA-II heterodimers. In the last years, some important insights on apoA-IM have been provided, i.e. that apoA-IM/apoA-IM has a very long permanence in blood, as well as a high capacity to remove tissue cholesterol, in addition to further attractive properties. These effects stimulated a number of attempts on alternative developments in high-density lipoprotein (HDL) therapy, i.e. to the so-called apoA-I mimetics. A frequent criticism, i.e. the lack of a detailed comparative assessment of the capacity of apoA-I versus apoA-IM in arterial cholesterol removal, has recently been overcome by a trial of gene therapy with apoA-IM versus wild-type apoA-I in hyperlipidemic mice. Structural studies on the dimer indicate that this very stable compound is present in small HDL, containing a single molecule of dimer, and apparently is responsible for the higher effectiveness of apoA-IM sera in mobilizing cholesterol from macrophages, when the ATP-binding cassette, subfamily A, member 1 (ABCA1)-driven efflux is stimulated. An additional protective trait of apoA-IM carriers is the peculiar susceptibility to proteolysis of the heterodimer, an interesting hypothetical mechanism for cardiovascular protection. The heterodimer would, in fact, act as a suicide substrate for arterial metalloproteinases, responsible for plaque rupture.Pubblicazioni consigliate
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