Radiation is a risk factor for atherosclerotic cardiovascular disease. However, little is known about the mechanisms that underlie radiation-enhanced atherosclerosis. Our recent studies have identified H2, the murine MHC, as a major genetic determinant of susceptibility to radiation-enhanced atherosclerosis. C3H/HeJ (C3H) mice are extremely resistant to atherosclerosis, developing much smaller lesions than C57BL/6 (B6) mice when deficient in apolipoprotein E (apoE-/-) or fed an atherogenic diet. The two strains differ in the H2 haplotype with B6 having H2b and C3H having H2k. C3.SW-H2b/SnJ (C3.SW) is a congenic strain of C3H/HeJ in which the H2k locus is replaced with H2b. Surprisingly, C3.SW.apoE-/- mice that underwent bone marrow transplantation after lethal irradiation exhibited a 21-fold increase in atherosclerotic lesion size relative to C3H.apoE-/- mice receiving the same treatment, demonstrating the dramatic impact of H2 haplotypes on atherosclerosis. We will use this novel C3.SW.apoE-/- mouse model to investigate mechanistic links between H2 haplotypes and plaque formation. We will also test a promising candidate gene in the H2 region. MDC1, encoding the mediator of DNA damage checkpoint 1, is a component of the genome surveillance network activated by DNA double-strand breaks. Multiple SNPs have been detected in both coding and regulatory regions of MDC1 between H2b and H2k haplotypes. We will determine whether deficiency in MDC1 would promote atherosclerosis following radiation. These studies will shed light on new genes and new pathways that control atherosclerosis susceptibility.

Public Health Relevance

Radiation therapy or radiotherapy is the most important non-surgical modality for the treatment of cancer and many proliferating, non-malignant conditions. However, patients receiving radiotherapy have an increased risk of developing atherosclerotic cardiovascular disease. The objective of this project is to identify genes in the major histocompatibility complex (MHC) region that have a dramatic influence on radiation-induced atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL112281-01
Application #
8240933
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2011-12-15
Project End
2013-11-30
Budget Start
2011-12-15
Budget End
2012-11-30
Support Year
1
Fiscal Year
2012
Total Cost
$231,000
Indirect Cost
$81,000
Name
University of Virginia
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904