Insulin-like growth factor I reduces lipid oxidation and foam cell formation via downregulation of 12/15-lipoxygenase

• Published in: Atherosclerosis 2015-02, Vol.238 (2), p.313-320
• Main Authors: Sukhanov, Sergiy, Snarski, Patricia, Vaughn, Charlotte, Lobelle-Rich, Patricia, Kim, Catherine, Higashi, Yusuke, Shai, Shaw-Yung, Delafontaine, Patrice
• Format: Article
• Language: English
• Subjects: Animals; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Arachidonate 12-Lipoxygenase - genetics; Arachidonate 12-Lipoxygenase - metabolism; Arachidonate 15-Lipoxygenase - genetics; Arachidonate 15-Lipoxygenase - metabolism; Atherosclerosis; Atherosclerosis - blood; Atherosclerosis - enzymology; Atherosclerosis - genetics; Atherosclerosis - pathology; Atherosclerosis - prevention & control; Cardiovascular; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Foam cells; Foam Cells - drug effects; Foam Cells - enzymology; Foam Cells - pathology; Gene Expression Regulation, Enzymologic; Insulin-Like Growth Factor I - administration & dosage; LDL/Oxidation/antioxidants; Lipoproteins, LDL - blood; Lipoproteins, LDL - metabolism; Lipoxygenase; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - enzymology; Macrophages, Peritoneal - pathology; Macrophages/monocytes; Mice, Inbred C57BL; Mice, Knockout; Oxidized lipids; Phosphatidylinositol 3-Kinase - metabolism; RNA, Messenger - metabolism; Signal Transduction - drug effects; STAT6 Transcription Factor - metabolism
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2014.12.024

Abstract Objective : We have shown that insulin-like growth factor I (IGF-1) infusion in Apoe−/− mice decreased atherosclerotic plaque size and plaque macrophage and lipid content suggesting that IGF-1 suppressed formation of macrophage-derived foam cells. Since 12/15-lipoxygenase (12/15-LOX) plays an important role in OxLDL and foam cell formation, we hypothesized that IGF-1 downregulates 12/15-LOX, thereby suppressing lipid oxidation and foam cell formation. Approach and Results : We found that IGF-1 decreased 12/15-LOX plaque immunopositivity and serum OxLDL levels in Apoe−/− mice. IGF-1 reduced 12/15-LOX protein and mRNA levels in cultured THP-1 macrophages and IGF-1 also decreased expression of STAT6 transcription factor. IGF-1 reduction in macrophage 12/15-LOX was mediated in part via a PI3 kinase- and STAT6-dependent transcriptional mechanism. IGF-1 suppressed THP-1 macrophage ability to oxidize lipids and form foam cells. IGF-1 downregulated 12/15-LOX in human blood-derived primary macrophages and IGF-1 decreased LDL oxidation induced by these cells. IGF-1 reduced LDL oxidation and formation of foam cells by wild type murine peritoneal macrophages, however these effects were completely blocked in 12/15-LOX-null macrophages suggesting that the ability of IGF-1 to reduce LDL oxidation and foam cells formation is dependent on its ability to downregulate 12/15-LOX. Conclusions : Overall our data demonstrate that IGF-1 reduces lipid oxidation and foam cell formation via downregulation of 12/15-LOX and this mechanism may play a major role in the anti-atherosclerotic effects of IGF-1.