Apolipoprotein A-I and the molecular variant apoA-I(Milano): evaluation of the antiatherogenic effects in knock-in mouse model.
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.
Parolini
Cinzia
C
Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy. cinzia.parolini@unimi.it
Chiesa
Giulia
G
Gong
Elaine
E
Caligari
Silvia
S
Cortese
Miriam M
MM
Koga
Teiichiro
T
Forte
Trudy M
TM
Rubin
Edward M
EM
D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D015153:Blotting, Western; D004247:DNA / Q000235:genetics; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009391:Nephelometry and Turbidimetry; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D012737:Sex Factors
D016632:Apolipoprotein A-I; C080631:apolipoprotein A-I Milano; D004247:DNA