ApoA‐I_Milano from structure to clinical application

Abstract

Apolipoprotein A‐I_Milano (apoA‐I_M) 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‐I_M have been provided, i.e. that apoA‐I_M/apoA‐I_M 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‐I_M in arterial cholesterol removal, has recently been overcome by a trial of gene therapy with apoA‐I_M 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‐I_M 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‐I_M 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.

• Animal model
• apolipoprotein A‐I_Milano
• cardiovascular risk
• high‐density lipoprotein (HDL)
• HDL therapy
• IVUS
• liposome
• phospholipid
• synthetic HDL
• transgenic mouse

Acknowledgements

This investigation was supported in part by grants from Università degli Studi di Milano (FIRST) and from MIUR (FIRB 2003).