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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL113705-02
Application #
8692010
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Olive, Michelle
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Tulane University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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