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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.

Original publication

DOI

10.1074/jbc.M108061200

Type

Journal article

Journal

J Biol Chem

Publication Date

08/02/2002

Volume

277

Pages

4505 - 4511

Keywords

Animals, Aorta, Arteriosclerosis, Disease Models, Animal, Hyperlipidemias, Insulin-Like Growth Factor II, Mice, Mice, Knockout, Microscopy, Electron, Transgenes