Insulin-like growth factor II plays a central role in atherosclerosis in a mouse model.
Insulin-like growth factor II is a fetal promoter of cell proliferation that is involved in some forms of cancer and overgrowth syndromes in humans. Here, we provide two sources of genetic evidence for a novel, pivotal role of locally produced insulin-like growth factor II in the development of atherosclerosis. First, we show that homozygosity for a disrupted insulin-like growth factor II allele in mice lacking apolipoprotein E, a widely used animal model of atherosclerosis, results in aortic lesions that are approximately 80% smaller and contain approximately 50% less proliferating cells compared with mice lacking only apolipoprotein E. Second, targeted expression of an insulin-like growth factor II transgene in smooth muscle cells, but not the mere elevation of circulating levels of the peptide, causes per se aortic focal intimal thickenings. The insulin-like growth factor II transgenics presented here are the first viable mutant mice spontaneously developing intimal masses. These observations provide the first direct evidence for an atherogenic activity of insulin-like growth factor II in vivo.
Zaina
Silvio
S
Experimental Cardiovascular Research, Wallenberg Laboratory, Department of Medicine, University of Lund, Malmö General Hospital, 205 02 Malmö, Sweden. silvis.zaina@medforsk.mas.lu.se
Pettersson
Linda
L
Ahrén
Bo
B
Brånén
Lena
L
Hassan
A Bassim
AB
Lindholm
Marie
M
Mattsson
Ragnar
R
Thyberg
Johan
J
Nilsson
Jan
J
D000818:Animals; D001011:Aorta / Q000473:pathology / Q000648:ultrastructure; D001161:Arteriosclerosis / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D006949:Hyperlipidemias / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D019076:Transgenes
D007335:Insulin-Like Growth Factor II