2009 Southern Regional Meeting Abstracts
Session: North American Joint Session - Cardiovascular I
INSULIN-LIKE GROWTH FACTOR I DOWNREGULATES LIPOPROTEIN LIPASE AND SUPPRESSES ATHEROSCLEROTIC FOAM CELL FORMATION IN VIVO AND IN VITRO
Sukhanov S, Vaughn C, Higashi Y, Shai S, Delafontaine P. Tulane University, New Orleans, LA.
Purpose of Study: We have shown that insulin-like growth factor I (IGF-1) decreases atherosclerotic burden in ApoE-null mice. Lipoprotein lipase (LPL) increases the uptake of oxidized low density lipoprotein (OxLDL) by macrophages (MΦ), promoting foam cell formation and atherosclerosis. The purpose of this study to determine a potential effect of IGF-1 on LPL and foam cell formation in vivo and in vitro.
Methods Used: ApoE-null mice were infused with IGF-1 (1.5 mg/kg) or saline for 12 weeks, foam cells were quantified by Oil Red positivity and MΦ - by immunostaining with Mac-3 a/b. LPL activity - fluorescence assay, gene expression - RT-PCR, LDL binding - fluorescent DiI-OxLDL assay and OxLDL uptake - Oil Red staining.
Summary of Results: IGF-1 reduced aortic LPL mRNA levels by 31% and serum LPL activity by 66%. This effect correlated with a 27% reduction in Oil Red-positive aortic valve lesion area and a 36% decrease in plaque MΦ levels suggesting that IGF-1 reduced MΦ-derived foam cell formation. To determine the role of IGF-1 and LPL in foam cell formation, human blood monocyte- or THP-1 cell-derived MΦ were treated with OxLDL (80 ug/ml, 48 h) to stimulate formation of Oil Red-positive “foam cells”. OxLDL increased MΦ LPL mRNA levels and LPL activity >5-fold and decreased MΦ IGF-1 receptor (IGF1R) levels by 65%. IGF-1 (25 ng/ml, 24h) reversed OxLDL-induced upregulation of LPL activity (52% inhibition) and decreased lipid uptake by 88%. Furthermore, overexpression of IGF1R in MΦ with an adenovirus encoding IGF1R prevented lipid uptake by 82% vs. control Ad-GFP-infected MΦ. Conversely, addition of 5 ug/ml exogenous LPL increased DiI-OxLDL binding by MΦ (2.3-fold increase) and lipid uptake (1.9-fold increase). Liver X receptor (LXR) is a nuclear transcription factor regulating MΦ LPL expression. The LXR agonist 22R-oxycholesterol (50 uM, 16h) markedly increased LPL activity in MΦ (>2-fold) and IGF-1 reversed this effect by 65%.
Conclusions: Our data indicate that IGF-1 downregulates LPL in vivo and in vitro potentially via a LXR-dependent mechanism and inhibits foam cell formation. This is the first report of an effect of IGF-1 on cellular lipid internalization and these findings have major relevance for the understanding of mechanisms whereby IGF-1 reduces atherosclerosis.
|
