Role of Interleukin-1 in Radiation-Induced Cardiomyopathy

Authors

Eleonora Mezzaroma, Virginia Commonwealth UniversityFollow
Ross B. Mikkelsen, Virginia Commonwealth UniversityFollow
Stefano Toldo, Virginia Commonwealth UniversityFollow
Adolfo G. Mauro, Virginia Commonwealth UniversityFollow
Khushboo Sharma, Virginia Commonwealth UniversityFollow
Carlo Marchetti, Virginia Commonwealth UniversityFollow
Asim Alam, Virginia Commonwealth UniversityFollow
Benjamin W. Van Tassell, Virginia Commonwealth UniversityFollow
David A. Gewirtz, Virginia Commonwealth UniversityFollow
Antonio Abbate, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2015

Journal/Book/Conference Title

Molecular Medicine

Volume

21

DOI of Original Publication

10.2119/molmed.2014.00243

Comments

Originally published at http://dx.doi.org/10.2119/molmed.2014.00243

Date of Submission

April 2016

Abstract

Thoracic X-ray therapy (XRT), used in cancer treatment, is associated with increased risk of heart failure. XRT-mediated injury to the heart induces an inflammatory response leading to cardiomyopathy. The aim of this study was to determine the role of interleukin (IL)-1 in response to XRT injury to the heart and on the cardiomyopathy development in the mouse. Female mice with genetic deletion of the IL-1 receptor type I (IL-1R1 knockout mice [IL-1R1 KO]) and treatment with recombinant human IL-1 receptor antagonist anakinra, 10 mg/kg twice daily for 7 d, were used as independent approaches to determine the role of IL-1. Wild-type (wt) or IL-1R1 KO mice were treated with a single session of XRT (20 or 14 gray [Gy]). Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson’s trichrome was used to assess myocardial fibrosis and pericardial thickening. After 20 Gy, the contractile reserve was impaired in wt mice at d 3, and the LV ejection fraction (EF) was reduced after 4 months when compared with sham-XRT. IL-1R1 KO mice had preserved contractile reserve at 3 d and 4 months and LVEF at 4 months after XRT. Anakinra treatment for 1 d before and 7 d after XRT prevented the impairment in contractile reserve. A significant increase in LV end-diastolic pressure, associated with increased myocardial interstitial fibrosis and pericardial thickening, was observed in wt mice, as well as in IL-1R1 KO–or anakinra-treated mice. In conclusion, induction of IL-1 by XRT mediates the development of some, such as the contractile impairment, but not all aspects of the XRT-induced cardiomyopathy, such as myocardial fibrosis or pericardial thickening.

Rights

Copyright 2015, The Feinstein Institute for Medical Research

Is Part Of

VCU Pharmacotherapy and Outcomes Science Publications