Abstract
Radiation-induced heart disease (RIHD), which is a serious side effect of the radiotherapy applied for various tumors due to the inevitable irradiation of the heart, cannot be treated effectively using current clinical therapies. Here, we demonstrated that rhNRG-1β, an epidermal growth factor (EGF)-like protein, protects myocardium tissue against irradiation-induced damage and preserves cardiac function. rhNRG-1β effectively ameliorated irradiation-induced myocardial nuclear damage in both cultured adult rat-derived cardiomyocytes and rat myocardium tissue via NRG/ErbB2 signaling. By activating ErbB2, rhNRG-1β maintained mitochondrial integrity, ATP production, respiratory chain function and the Krebs cycle status in irradiated cardiomyocytes. Moreover, the protection of irradiated cardiomyocytes and myocardium tissue by rhNRG-1β was at least partly mediated by the activation of the ErbB2-ERK-SIRT1 signaling pathway. Long-term observations further showed that rhNRG-1β administered in the peri-irradiation period exerts continuous protective effects on cardiac pump function, the myocardial energy metabolism, cardiomyocyte volume and interstitial fibrosis in the rats receiving radiation via NRG/ErbB2 signaling. Our findings indicate that rhNRG-1β can protect the myocardium against irradiation-induced damage and preserve cardiac function via the ErbB2-ERK-SIRT1 signaling pathway.
Highlights
Radiation-induced heart disease (RIHD) is one of the important long-term side effects of radiotherapy for thoracic tumors, breast cancer, chest wall tumors and lymphoma when all or part of the heart is exposed to ionizing radiation [1, 2]
To investigate whether rhNRG-1β influences the cardiomyocyte injury caused by irradiation, irradiated cardiomyocytes were subjected to immunofluorescence staining for γH2AX 6 h after irradiation (Fig 1A, S1A Fig)
When cardiomyocytes were exposed to Herceptin before rhNRG-1β treatment, the protection of cells against radiation-induced injury by rhNRG-1β was nearly abolished (H +NRG, P0.05 versus Vehicle; n = 5 per group), indicating that rhNRG-1β functions via ErbB2
Summary
Radiation-induced heart disease (RIHD) is one of the important long-term side effects of radiotherapy for thoracic tumors, breast cancer, chest wall tumors and lymphoma when all or part of the heart is exposed to ionizing radiation [1, 2]. The resultant conditions can include pericardial and atherosclerosis, myocardial infarction, cardiac valve injuries, myocardial fibrosis, and conduction abnormalities. Numerous studies addressing RIHD suggest that radiation causes micro- and macro-vascular endothelial inflammatory responses, which can trigger vascular damage and myocardial degeneration [1, 3]. RhNRG-1β Protects the Myocardium against Irradiation-Induced Damage endocardium and endothelial cells of the myocardial microvasculature regulate the proliferation, maturation, injury and regeneration of the myocardium through multiple paracrine signaling pathways [4]. Few studies focus on the cross-talk between the endocardium and myocardium in RIHD
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