RhNRG-1β Protects the Myocardium against Irradiation-Induced Damage via the ErbB2-ERK-SIRT1 Signaling Pathway

PLOS ONE, Dec 2019

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.

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RhNRG-1β Protects the Myocardium against Irradiation-Induced Damage via the ErbB2-ERK-SIRT1 Signaling Pathway

September RhNRG-1β Protects the Myocardium against Irradiation-Induced Damage via the ErbB2-ERK-SIRT1 Signaling Pathway Anxin Gu 0 1 2 Yamin Jie 0 1 2 Liang Sun 0 1 2 Shuping Zhao 0 1 2 Mingyan E 0 1 2 Qingshan You 0 1 2 0 1 Department of Radiotherapy, the Affiliated Tumor Hospital of Harbin Medical University , Harbin, Heilongjiang , China , 2 Department of Radiotherapy, the Fourth Affiliated Hospital of Harbin Medical University , Harbin, Heilongjiang , China , 3 Department of Human Anatomy, Harbin Medical University , Harbin, Heilongjiang , China 1 Funding: This work was supported by Heilongjiang Province Science and Technology Project Fund , GC07C354; to ME 2 Editor: Guo-Chang Fan, University of Cincinnati, College of Medicine, UNITED STATES 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 irradiationinduced 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. - Competing Interests: The authors have declared that no competing interests exist. 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]. In addition, many studies indicate that the endocardium and endothelial cells of the myocardial microvasculature regulate the proliferation, maturation, injury and regeneration of the myocardium through multiple paracrine signaling pathways [4]. However, few studies focus on the cross-talk between the endocardium and myocardium in RIHD. Neuregulin (NRG)-1/ErbB2 signaling is one of the important pathways that mediates the cross-talk between the endocardium and myocardium [5, 6]. NRG-1 is a member of the neuregulin family that is synthesized and expressed in the endocardium and the endothelial cells of the myocardial microvasculature. NRG-1 gene encodes more than 14 soluble and transmenbrane protein products [5]. In mammalian myocardium tissue, soluble NRG-1 isoforms (mainly NRG-1β) released from the proteolysis of the extracellular domain of transmembrane NRG-1 isoforms function as a paracrine signaling molecule that binds the tyrosine kinase receptor ErbB4 and activates ErbB4 and its coreceptor ErbB2 co-expressed on adjacent cardiomyocytes [6, 7]. Although unable to directly bind ligands including NRG-1β, ErbB2 serving as the preferred heterodimerization partner for ErbB4 is essential for the stabilization of ligand binding and ligand-induced receptor signaling transduction [8, 9]. When activated by NRG-1, ErbB2 signaling promotes the survival and proliferation of cardiomyocyte, preserves the myocardial sarcomeric structure, maintains intracellular Ca2+ homeostasis and enhances cardiac pump function, which is considered to be a prospective target in the treatment of heart damage [10, 11]. Based on these findings, a 61-amino acid recombinant human neuregulin-1β protein (rhNRG-1β), which is encoded by the NRG gene and contains an immunoglobulin domain and the EGF-like domain necessary for ErbB2/ErbB4 activation, has been applied in preclinical and clinical studies of heart disease treatment. In preclinical studies, rhNRG-1β improved cardiomyocyte survival and cardiac function in models of dilated cardiomyopathy and ischemic, viral and doxorubicin-induced heart damage [7, 9, 12–14]. Recently, rhNRG-1β was demonstrate (...truncated)


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Anxin Gu, Yamin Jie, Liang Sun, Shuping Zhao, Mingyan E, Qingshan You. RhNRG-1β Protects the Myocardium against Irradiation-Induced Damage via the ErbB2-ERK-SIRT1 Signaling Pathway, PLOS ONE, 2015, Volume 10, Issue 9, DOI: 10.1371/journal.pone.0137337