Abstract
Neuregulin-1 (NRG-1), a cardioactive growth factor released from endothelial cells, has been shown to be indispensable for the normal function of the adult heart by binding to ErbB4 receptors on cardiomyocytes. In the present study, we have investigated to what extent ErbB2, the favored co-factor of ErbB4 for heterodimerization, participates in the cardiac effects of endothelium-derived NRG-1. In addition, in view of our previously described anti-adrenergic effects of NRG-1, we have studied which neurohormonal stimuli affect endothelial NRG-1 expression and release and how this may fit into a broader frame of cardiovascular physiology. Immunohistochemical staining of rat heart and aorta showed that NRG-1 expression was restricted to the endocardial endothelium and the cardiac microvascular endothelium (CMVE); by contrast, NRG-1 expression was absent in larger coronary arteries and veins and in aortic endothelium. In rat CMVE in culture, NRG-1 mRNA and protein expression was down-regulated by angiotensin II and phenylephrine and up-regulated by endothelin-1 and mechanical strain. CMVE-derived NRG-1 was shown to phosphorylate cardiomyocyte ErbB2, an event prevented by a 24-h preincubation of myocytes with monoclonal ErbB2 antibodies. Pretreating cardiomyocytes with these inhibitory anti-ErbB2 antibodies significantly attenuated CMVE-induced cardiomyocyte hypertrophy and abolished the protective actions of CMVE against cardiomyocyte apoptosis. Accordingly, ErbB2 signaling participated in the paracrine survival and growth controlling effects of NRG-1 on cardiomyocytes in vitro, explaining the cardiotoxicity of ErbB2 antibodies in patients. Cardiac NRG-1 synthesis occurs in endothelial cells adjacent to cardiac myocytes and is sensitive to factors related to the regulation of blood pressure.
Highlights
Whereas NRG-1 has been detected in the endothelium [1]
We have investigated the role of ErbB2 in the hypertrophic and anti-apoptotic effects mediated by the cardiac endothelium through experiments with endothelium-cardiomyocyte co-cultures or endothelium-conditioned medium and with recombinant NRG-1 as a positive control
We investigated the role of endothelium-derived NRG-1 in the paracrine hypertrophic effects of cardiac microvascular endothelium (CMVE) on cardiomyocytes by analyzing (i) cardiomyocyte hypertrophy induced by medium conditioned by CMVE and (ii) cardiomyocyte hypertrophy induced by coculture with CMVE, both in the presence and absence of the inhibitory anti-ErbB2 antibody
Summary
Whereas NRG-1 has been detected in the endothelium [1]. Binding of NRG-1 to its receptor induces the formation of homo- and heterodimers, which is crucial for signaling [2]. We have investigated the role of ErbB2 in the hypertrophic and anti-apoptotic effects mediated by the cardiac endothelium through experiments with endothelium-cardiomyocyte co-cultures or endothelium-conditioned medium and with recombinant NRG-1 as a positive control.
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