Atherosclerosis is the principal underlying cause of most cardiovascular disease-related deaths and there is a great need to develop innovative therapies targeting overall disease burden and to decrease acute vascular events related to plaque instability. Atherosclerosis is an inflammatory disease in which macrophages and macrophage-derived foam cells play a pre-dominant role. Recent findings indicate that insulin-like growth factor-1 (IGF-1) reduces atherosclerotic burden and increases features of plaque stability in Apoe-/- mice and these effects correlate with reduced plaque macrophages and lipid levels and decreased foam cells. However, mechanisms whereby IGF-1 exerts vasculoprotective effects are unclear. The goal of this exploratory project is to determine mechanism whereby IGF-1 alters lipid uptake in macrophages and reduces atherosclerotic burden. My preliminary data demonstrate that IGF-1 downregulates 12/15-lipoxygenase (12/15- LOX) expression in Apoe-/- mice and in cultured macrophages. The latter effect correlates with decreased cell- mediated lipid oxidation and reduced lipid uptake. 12/15-LOX mediates the transformation of low density lipoprotein into its oxidized form and via this mechanism 12/15-LOX enhances macrophage lipid uptake and promotes formation of foam cells. I will focus this short-term R21 exploratory proposal on studying the transcriptional mechanism of IGF-1-induced 12/15-LOX regulation in macrophages and I will also determine the importance of IGF-1 downregulation of 12/15-LOX and the specific role of macrophage 12/15-LOX for its anti-atherosclerotic effect. The central hypothesis is that IGF-1 downregulates 12/15-LOX in macrophages via reduced expression and/or activity of STAT-6 transcription factor. This suppression of macrophage 12/15-LOX is critical for IGF-1-induced reduction in atherosclerotic plaque burden.
Two specific aims have been designed:
Specific Aim 1. To study the transcriptional mechanism mediating IGF-1-induced downregulation of 12/15-LOX in macrophages.
Specific Aim 2. To study whether 12/15-LOX downregulation mediates IGF-1-induced reduction in atherosclerotic plaque burden. Expected outcome: I anticipate that IGF-1-induced suppression of STAT-6 will downregulate macrophage 12/15-LOX and this mechanism will mediate the reduced macrophage lipid uptake. I expect to demonstrate that macrophage-specific 12/15-LOX is the critical mediator of IGF-1-induced anti-atherosclerotic effects in Apoe-/- mice. Overall, these findings will establish the role of 12/15-LOX as a key component of IGF-1-induced suppression of macrophage lipid uptake in vitro and IGF-1-induced atheroprotection in Apoe-/- mice. The anticipated results of this R21 will serve as essential experimental support for the preparation of a future full- scale (R01) proposal focusing on studying cell-targeted effects of IGF-1. In addition, I anticipate that identification of molecular mechanisms regulating 12/15-LOX expression will offer new targets for therapeutic intervention.
Acute cardiovascular events are mostly caused by unstable atherosclerotic plaque rapture. We propose to study effects of growth factor called IGF-1 which is capable to reduce the atherosclerotic plaque size and increase plaque stability in animal model. If applied to humans this approach will be a breakthrough that reduces the incidence of acute cardiovascular events.
|Blackstock, Christopher D; Higashi, Yusuke; Sukhanov, Sergiy et al. (2014) Insulin-like growth factor-1 increases synthesis of collagen type I via induction of the mRNA-binding protein LARP6 expression and binding to the 5' stem-loop of COL1a1 and COL1a2 mRNA. J Biol Chem 289:7264-74|
|Higashi, Yusuke; Quevedo, Henry C; Tiwari, Summit et al. (2014) Interaction between insulin-like growth factor-1 and atherosclerosis and vascular aging. Front Horm Res 43:107-24|