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.In the adult heart, the neuregulin (NRG) 3 receptors ErbB2 and ErbB4, but not ErbB3, are found on cardiomyocytes, 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). Although NRG-1 does not bind directly to ErbB2, it is the favored co-receptor for heterodimerization (3). This means that, in the adult heart, NRG-1 signaling can occur through ErbB2/ErbB4 heterodimers and/or ErbB4/ErbB4 homodimers. The importance of NRG/ErbB signaling in the adult heart was revealed by an unforeseen side effect of trastuzumab (Herceptin), a monoclonal antibody against ErbB2 used in the treatment of breast cancer. Unexpectedly, trastuzumab induced dilated cardiomyopathy and heart failure in human patients when combined with a treatment of anthracycline (4, 5). In addition, postnatal conditional mutation of cardiac ErbB2 leads to dilated cardiomyopathy in the mouse (6).Despite these observations, the specific role of ErbB2 in the cardioprotective actions of NRG-1 has remained controversial. Hence, the interpretation of the cardiotoxic effects of trastuzumab in patients has remained difficult. For example, Grazette et al. (7) indica...

. Mesenchymal stem cell adhesion to cardiac microvascular endothelium: activators and mechanisms.

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In obese Type 2 diabetic mice, in the absence of hypoglycaemic effects, inhibition of DPP-4 decreases LV passive stiffness and improves global LV performance. These effects seem at least partially mediated by stimulatory effects on the myocardial cGMP-PKG pathway and, hence, on the phosphorylation status of titin and the hereto coupled cardiomyocyte stiffness modulus.

The whole cell mode of the patch-clamp technique was applied to cultured endocardial endothelial cells from the porcine right ventricle to study their electrophysiological properties. With isotonic pipette and bathing solutions (300-310 mosmol/kgH2O), single endocardial endothelial cells had resting membrane potentials ranging from -20 to -90 mV (mean = -55 +/- 20 mV, n = 48). In voltage-clamp experiments, the main membrane current was an inwardly rectifying K+ current with all characteristics described for the inwardly rectifying K+ current in vascular endothelium. Outward currents at positive clamp potentials were small, but when cell swelling was induced by means of a hypertonic pipette or hypotonic bathing solution and ATP (5 mM) was present in the pipette solution, a large outwardly rectifying current developed. This volume-activated current was insensitive to extracellular K+ or Na+ concentration variations but sensitive to changes in extracellular Cl- concentrations. It was inhibited in the presence of 4,4'-diisothiocyanostilbene-2,2 disulfonic acid (100-300 microM) and flufenamic acid (50-100 microM). Volume-activated Cl- channels are different from the stretch-activated cationic channels described in vascular endothelium and might be involved in the regulation of cell volume or the response to mechanical stretch.

The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl

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