Role of the bradykinin B2 receptor in a rat model of local heart irradiation

Abstract

Purpose: Radiation-induced heart disease (RIHD) is a delayed effect of radiotherapy for cancers of the chest, such as breast, esophageal, and lung. Kinins are small peptides with cardioprotective properties. We previously used a rat model that lacks the precursor kininogen to demonstrate that kinins are involved in RIHD. Here, we examined the role of the kinin B2 receptor (B2R) in early radiation-induced signaling in the heart.

Materials and methods: Male Brown Norway rats received the B2R-selective antagonist HOE-140 (icatibant) via osmotic minipump from 5 days before until 4 weeks after 21 Gy local heart irradiation. At 4 weeks, signaling events were measured in left ventricular homogenates and nuclear extracts using western blotting and real-time polymerase chain reaction. Numbers of CD68-positive (monocytes/macrophages), CD2-positive (T-lymphocytes), and mast cells were measured using immunohistochemistry.

Results: Radiation-induced c-Jun phosphorylation and nuclear translocation were enhanced by HOE-140. HOE-140 did not modify endothelial nitric oxide synthase (eNOS) phosphorylation or alter numbers of CD2-positive or mast cells, but enhanced CD68-positive cell counts in irradiated hearts.

Conclusions: B2R signaling may regulate monocyte/macrophage infiltration and c-Jun signals in the irradiated heart. Although eNOS is a main target for kinins, the B2R may not regulate eNOS phosphorylation in response to radiation.

Keywords::

• Bradykinin
• B2 receptor
• c-Jun
• heart
• macrophages

Acknowledgements

This work was supported by grant funding from the National Institutes of Health (CA148679) and American Cancer Society (RSG-10-125-01-CCE). The authors would like to acknowledge Howard Hendrickson, PhD, for his technical assistance with the HPLC studies.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Supplementary material available online

Supplementary Figures 1–6 available online at http://informahealthcare.com/abs/doi/10.3109/09553002.2015.1047041.