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

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

doi:10.1016/j.atherosclerosis.2005.03.008

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Volume 183, Issue 2 , Pages 222-229, December 2005

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

Cinzia Parolini
- Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy
- Corresponding author. Tel.: +39 02 50318328; fax: +39 02 50318284.
Giulia Chiesa
- Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy
Elaine Gong
- Genome Sciences Department, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Silvia Caligari
- Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy
Miriam M. Cortese
- Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy
Teiichiro Koga
- Genome Sciences Department, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Trudy M. Forte
- Genome Sciences Department, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
Edward M. Rubin
- Genome Sciences Department, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

Received 16 September 2004; received in revised form 1 March 2005; accepted 14 March 2005.

Abstract

No evidence of premature vascular disease is found in apolipoprotein A-I_Milano (apoA-I_M) human carriers, despite very low high density lipoprotein (HDL) cholesterol levels. Whether apoA-I_M may impart a “gain of function” in atherosclerosis protection compared to wild-type apoA-I is hotly debated. To address this question, knock-in mice expressing human apoA-I or apoA-I_M were crossed with atherosclerosis-susceptible mice expressing the human apoB/A-II transgene (h-B/A-II/A-I^Hu/Hu and h-B/A-II/A-I_M^Hu/Hu). On a chow diet, h-B/A-II/A-I_M^Hu/Hu mice were characterized by low HDL cholesterol levels compared to h-B/A-II/A-I^Hu/Hu mice (35.65±8.00mg/dl versus 58.09±13.50mg/dl, respectively; p<0.005). Gender differences in response to high fat diet were observed in both h-B/A-II/A-I_M^Hu/Hu and h-B/A-II/A-I^Hu/Hu lines. h-B/A-II/A-I_M^Hu/Hu females had higher total cholesterol levels compared to h-B/A-II/A-I^Hu/Hu females (895.08±183.07mg/dl versus 544.43±116.42mg/dl; p<0.05) and developed larger atherosclerotic lesions (148,260±78,924μm² versus 54,132±43,204μm², respectively; p<0.05). On the contrary, no difference in mean lesion area was found between h-B/A-II/A-I_M^Hu/Hu and h-B/A-II/A-I^Hu/Hu males (19,779±6098μm² versus 15,706±13,095μm²; p=0.685). Our data suggest that, in the atherosclerosis-susceptible human apoB/A-II mouse model, expression of the human apoA-I_M gene does not have protective advantage over that of the apoA-I gene.