Radiation injury to the heart may occur in the context of radiation therapy (XRT) for various malignancies. While the initial (acute) injury to the heart must, of necessity, occur shortly after XRT, latent disease is generally not evident for many years, With the increasing success of cancer treatments, more patients with prior XRT will have a normal (or near-normal) life expectancy and may now be at risk for long-term complications of XRT. Interleukin-1 (IL-1), in the two forms ? and ?, is the prototypical cytokine involved in virtually every inflammatory response. Exogenous administration of IL-1? induces left ventricular systolic dysfunction in the mouse and impairs contractile reserve, reproducing a phenotype of heart failure in experimental models of acute myocardial infarction (AMI). The initial injury induces loss of viable myocardium, which prompts a maladaptive remodeling process (adverse remodeling) characterized by progressive cardiac enlargement and dysfunction, leading to heart failure and cardiac death. Mice with genetic deletion of the IL-1RI have a significantly more favorable profile of cardiac remodeling (less enlargement and dysfunction) following AMI. Both pharmacological and genetic inhibition of IL-1? (using recombinant human IL-1Ra [anakinra], IL-1Trap and antibody against IL-1?) limit the adverse remodeling process, and improve survival. We propose that blocking IL-1 with anakinra may represent a strategy to prevent, limit or treat XRT-induced cardiomyopathy. This proposal has two specific aims. The first is to determine whether increased IL-1 activity (early or late) after XRT exposure contributes to the development of cardiomyopathy in the mouse and whether genetic inhibition of IL-1 signaling can ameliorate the development of XRT-induced cardiomyopathy. The second is to determine whether a pharmacological blockade of IL-1 signaling affects the development of XRT-induced cardiomyopathy in the mouse. Our proposed studies are designed to elucidate the basis for the development of XRT-induced cardiomyopathy with the dual goals of identifying therapeutic strategies for preventing the development of this disease state and rescuing patients in whom the disease would otherwise develop as a consequence of previous radiation treatment.

Public Health Relevance

Our proposed studies are designed to elucidate the basis for the development of radiation-induced cardiomyopathy with the dual goals of identifying therapeutic strategies for preventing the development of this disease state and rescuing patients in whom the disease would otherwise develop as a consequence of previous radiation treatment. Both pharmacological and genetic inhibition of IL-1 (using recombinant human IL- 1 [anakinra], and IL1-receptor knockout mice) will be utilized to establish proof of principal that suppression of IL-1 signaling could be an effective strategy to prevent, limit or treat XRT-induced cardiomyopathy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA171974-01A1
Application #
8589054
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (M2))
Program Officer
Prasanna, Pat G
Project Start
2013-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$194,354
Indirect Cost
$63,854
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Toldo, Stefano; Mezzaroma, Eleonora; O'Brien, Laura et al. (2014) Interleukin-18 mediates interleukin-1-induced cardiac dysfunction. Am J Physiol Heart Circ Physiol 306:H1025-31