The possible role of iron in the promotion of atherosclerosis is a major unresolved question. Various studies in animal models and humans over the last 30 years assessed the effect of increased body iron on atherosclerosis but have yielded inconsistent results. In the last decade, our understanding of iron biology underwent a radical revision, raising questions about the design and interpretation of numerous studies on the subject. We will use the new understanding of iron homeostasis to explore the role of iron in atherosclerosis. Research focused on cardiovascular disease and nutrition areas with inconclusive evidence of benefit or risk has been identified as a high priority as indicated in a recent NIH initiative (PA-09-244). We propose to test the following conceptual framework. Iron, known as a potent catalyst for generation of reactive oxygen species, likely accelerates atherosclerosis by increasing oxidative stress in the plaque, oxidizing accumulated lipids and promoting inflammation. In atherosclerosis, as in other inflammatory diseases, systemic and local inflammation increases the production of the iron-regulatory peptide hormone hepcidin. Hepcidin functions by inhibiting the release of iron from macrophages, and would have the same effect in the atherosclerotic plaque on macrophages that ingest erythrocytes and apoptotic/necrotic cells. The hepcidin-mediated accumulation of iron in plaque macrophages and the resulting inflammation constitutes a self-amplifying process and is an important promoter of atherosclerosis.
Our specific aims are: 1. Define the effect of atherosclerosis on systemic (hepatic) and local (plaque macrophage) hepcidin production in apoE-/- mice 2. Define the effect of increased macrophage iron on atherosclerosis progression in flatiron mice on apoE-/- background Successful completion of this study will help resolve important questions about the role of iron in atherosclerosis. Similar to other modifiable risk factors, strategies for reduction of plaque iron could be devised to help reduce the morbidity and mortality associated with cardiovascular disease.

Public Health Relevance

Atherosclerosis is the leading cause of death in developed countries. Understanding the risk factors for this disease is a high priority. Building on recent advances in the field of iron metabolism, we propose to test how iron accumulation in atherosclerotic plaques promotes cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL106374-02
Application #
8208174
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Hasan, Ahmed AK
Project Start
2011-01-01
Project End
2012-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$154,000
Indirect Cost
$54,000
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Kautz, Léon; Gabayan, Victoria; Wang, Xuping et al. (2013) Testing the iron hypothesis in a mouse model of atherosclerosis. Cell Rep 5:1436-42