Apolipoprotein A-I and the molecular variant apoA-I(Milano): evaluation of the antiatherogenic effects in knock-in mouse model.

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+/-8.00 mg/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+/-183.07 mg/dl versus 544.43+/-116.42 mg/dl; p<0.05) and developed larger atherosclerotic lesions (148,260+/-78,924 microm(2) versus 54,132+/-43,204 microm(2), 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+/-6,098 microm(2) versus 15,706+/-13,095 microm(2); 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.

• Authors: Cinzia Parolini, Giulia Chiesa, Elaine Gong, Silvia Caligari, Miriam M Cortese, Teiichiro Koga, Trudy M Forte, Edward M Rubin
• Journal: Atherosclerosis (Atherosclerosis) Vol. 183 Issue 2 Pg. 222-9 (Dec 2005) ISSN: 0021-9150 [Print] Ireland
• PMID: 16285990 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Apolipoprotein A-I
• apolipoprotein A-I Milano
• DNA

Topics

• Animals
• Apolipoprotein A-I (blood, genetics)
• Atherosclerosis (blood, genetics, pathology)
• Blotting, Western
• DNA (genetics)
• Diet, Atherogenic
• Disease Models, Animal
• Female
• Gene Expression
• Genotype
• Humans
• Male
• Mice
• Mice, Knockout
• Nephelometry and Turbidimetry
• Polymerase Chain Reaction
• Risk Factors
• Sex Factors