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J. Biol. Chem., Vol. 281, Issue 28, 19469-19477, July 14, 2006

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Role of Neuregulin-1/ErbB2 Signaling in Endothelium-Cardiomyocyte Cross-talk^*

From the Department of Physiology, University of Antwerp, Antwerp 2020, Belgium

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.

Received for publication, January 17, 2006 , and in revised form, March 31, 2006.

^* This study was supported by the Belgian Science Policy (Project IAP-P5/02) and by the Fund for Scientific Research-Flanders (Project G.0131.05). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a grant from the Fund for Scientific Research-Flanders (Belgium).

² To whom correspondence should be addressed: University of Antwerp, Laboratory of Physiology Groenenborgerlaan 171, Bldg. V, 6th Fl., 2020 Antwerp, Belgium. Tel.: 32-3-265-32-77; Fax: 32-3-265-32-76; E-mail: gilles.dekeulenaer{at}ua.ac.be.

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