Department of Physiology, University College Cork, Cork, Republic of Ireland
Correspondence to Edward J. Johns, BSc, PhD, DSc, Department of Physiology, Western Gateway Building, University College Cork, Cork, Republic of Ireland. Tel: +021 420 5866; fax: +021 420 5977; e-mail: email@example.com
Neuregulin-1 (NRG-1) is one of a family of neurotrophic factors that act in a paracrine fashion by binding to ErbB2–4 receptor complexes which are widely expressed in many tissues of the body, including the cardiovascular and nervous systems . As such, this paracrine system is increasingly acknowledged as an important signalling cascade system that ensures a dynamic regulation and adjustment of cell processes necessary during development for normal functioning of tissues and organs and in response to injury and repair.
The NRG-1/ErbB signalling cascade exerts an important action on cellular processes necessary to ensure an integrated response to physiological activities in the vascular system and the heart. At an early stage, investigation into the role of the NRG-1/ErbB signalling pathway was directed towards its contribution to angiogenesis. It was found that in both in-vivo and in-vitro studies that the cascade pathway could stimulate endothelial cells to induce an angiogenic activity for revascularization of ischaemic tissue . Recognition of this important action led to the development of the monoclonal antibody against ErbB, trastuzumab, and although it proved effective [3,4] as an antiangiogenic drug, its use was associated with a raised incidence of cardiovascular morbidity which has brought into question its future therapeutic potential . These findings with trastuzumab have refocused attention on how the NRG-1/ErbB pathway impacts on the heart and its function in patho-physiological states. Early studies had revealed that the NRG-1/ErbB pathway was an essential component in allowing cardiac development during embryogenesis as disruption of the NRG-1 or ErbB genes led to malformation of the heart, which was lethal in utero. In terms of the adult heart, it became apparent that the NRG-1/ErbB pathway was essential for maintaining normal cardiac muscle integrity in response to varying demands on cardiac output. Both animal and human studies [6,7] have demonstrated ErbB2 and ErbB4 mRNA levels to be suppressed in cardiac myopathies and cardiac failure and although NRG-1 expression and production may initially increase, as the condition progresses, its production may decrease. Studies of this nature have led to the view that the NRG-1/ErbB pathway was essential for the maintenance of cardiac tissue integrity in patho-physiological states, which has opened the way to the development of recombinant human NRG-1. This compound has been found to improve cardiac integrity and function in animal models of heart failure. Moreover, it is now undergoing evaluation in man and a number of clinical trails have been undertaken in patients with systolic heart failure  and congestive heart failure  and have demonstrated significant improvement in cardiac function.
There is also an extensive distribution of the NGR-1/ErbB though both the central and peripheral nervous systems. There is a growing view that this signalling pathway may be important in neurotropic mechanisms and neuroprotection with both a short and long-term time frame [10,11]. An important function is that it acts as a mediator of repair as in many brain injury models, for example cerebral ischaemia and traumatic injury, NRG-1 and ErbB receptors are upregulated whilst exogenous NRG-1 administration enhances recovery of the anatomical and functional indices of injury. A further important action is that the NRG-1/ErbB system is involved in axon/Schwann cell interactions allowing the appropriate myelination process to take place. At the level of the central nervous system, the NRG-1/ErbB signalling cascade causes neuronal differentiation, migration and development by means of stimulating dendritic outgrowth. It is evident that activation of this pathway can increase the density and expression of potassium channels in the membranes of immature cerebellar cells , which has the potential of altering the excitability of neurones. Many of these studies have focused on the more long-term actions of the NRG-1/ErbB pathway, but there is evidence that local microinjection of NRG-1 onto RVLM neurones acutely depressed blood pressure, heart rate and renal sympathetic nerve activity whilst similar administration of ErbB antagonists led to increases in these variables .
It is important to appreciate that both at the heart and within the central nervous system in the disease process, the NRG-1/ErbB paracrine system has been shown to be a significant feature of the repair process. The report by Matsukawa et al. , published in this issue of the Journal attempts to gain a fuller appreciation of the role of NRG-1/ErbB within the brain when given chronically. It builds on their earlier observations  that the NRG-1/ErbB pathway has an important acute modulatory action at the level of the rostral venterolateral medulla (RVLM). This was investigated using a model of cardiac failure in which there is an activation of the sympathetic nervous system with a view to determining whether there was a consequent improvement in cardiac function.
The approach taken was to induce cardiac impairment using abdominal aortic banding above the level of the renal arteries, which is a pressure overload model. Over the 15 weeks of aortic banding there was a gradual deterioration in cardiac function consistent with the development of heart failure, and there was a sympatho-excitation as reflected by an increase in urinary noradrenaline excretion. Importantly, in these models, the gradual increase in sympathetic drive to the heart occurs to ensure an adequate cardiac output but the consequence is that it causes a further deterioration in function and a worsening of the cardiac failure. The question addressed by the authors was whether under these conditions, chronic application of NRG-1 locally within the brain, which might suppress the sympathetic drive, would therefore allow the function of the heart to improve. Over the 15 weeks following the aortic banding there was a progressive impairment of cardiac function in terms of left ventricular wall thickness, left ventricular end diastolic diameter and fractional shortening. This was associated with an increased urinary noradrenaline excretion at weeks 10 and 15 consistent with increased sympathetic activity. Interestingly, EbrB2, but not EbrB4, expression in the brainstem was reduced 5 weeks after aortic banding whereas NRG-1 expression was only decreased in the later phase from week 10. These observations clearly demonstrated that over the longer term, the deterioration in cardiac function was linked not only to a suppression of the NRG-1/EbrB signalling cascade in important brain areas, but to a sympatho-excitation. Their investigation was then directed to examine whether replacement of NRG-1 with a human recombinant NRG-1 infusion, given intracisternally to reactivate the pathway, would ameliorate the sympatho-excitation and improve cardiac function. Indeed, this proved to be the case as after 8 weeks of hrNRG-1 administration, endogenous NRG-1 and EbrB2 expression in the brainstem was restored to levels seen in the sham-operated animals. Moreover, there were corresponding functional correlates in that the marker for sympathetic activity, urinary noradrenaline, was reduced to normal levels but also cardiac function was improved. Together, these findings have provided strong evidence for a significant role for the NRG-1/EbrB axis within the brainstem in the regulation of inappropriate sympathetic drive in heart failure.
A number of important issues arise from these observations. One is whether this activation of the NRG-1/EbrB cascade with exogenous NRG-1 within the brainstem might be an important novel target for drug development in heart failure to remove the elevated sympathetic drive under these conditions. Intriguingly, the authors also used high doses of the rhNRG-1 given intraperitoneally as a control and this also activated the NRG-1 and EbrB2 expression in the brainstem. There are two points that arise from this observation; firstly, this suggests that the rhNRG-1 was able to cross the blood–brain barrier; secondly, what was not reported was how the NRG-1/EbrB signalling pathway within the heart following the aortic banding was altered and whether the intraperitoneal dose of rhNRG-1 normalized any derangement of the cascade within the heart. Thus, what remains unresolved is whether the systemic action of the rhNRG-1 to improve cardiac function resulted from an action at the heart or whether it was the action in the brain to reduce the sympathetic outflow, or possibly a combination of both these mechanisms.
At a more general level, it is becoming apparent that in terms of cardiovascular disorders associated with a raised sympathetic nervous activity, such as hypertension, heart failure and even renal failure, manipulation of signalling cascades within the brain may open up new areas for therapeutic development. This would have to occur alongside strategies designed to ensure that compounds are targeted selectively to the brain. Thus, whereas the study by Matsukawa et al. in this issue of the Journal has focused on the NRG-1/ErbB signalling pathway, others have undertaken the manipulation of G-protein ligand binding proteins, at the level of Gαi2 subunits [15–17] to demonstrate significant modulation of sympathetic output. Indeed, this particular point has been made previously by this group . This report by Matuskawa et al. may open up an important way forward for further exploration into devising means by which the sympathetic nervous system can be manipulated in a way to remove its contribution to the dysregulation of the cardiovascular system during the disease process and thereby interrupt its progression.
Conflicts of interest
There are no conflicts of interest.
1. Odiete O, Hill MF, Sawyer DB. Neuregulin in cardiovascular development and disease. Circ Res
2. Bagheri-Yarmand R, Vadlamudi RK, Wang RA, Mendelsohn J, Kumar R. Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis. J Biol Chem
3. Lange T, Nentwich MF, Luth M, Yekebas E, Schumacher U. Trastuzumab has antimetastatic and antiangiogenic activity in a spontaneous metastasis xenograft model of esophageal adenocarcinoma. Cancer Lett
4. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med
5. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol
6. Rohrbach S, Niemann B, Silber RE, Holtz J. Neuregulin receptors erbB2 and erbB4 in failing human myocardium: depressed expression and attenuated activation. Basic Res Cardiol
7. Rohrbach S, Yan X, Weinberg EO, Hasan F, Bartunek J, Marchionni MA, Lorell BH. Neuregulin in cardiac hypertrophy in rats with aortic stenosis. Differential expression of erbB2 and erbB4 receptors. Circulation
8. Gao R, Zhang J, Cheng L, Wu X, Dong W, Yang X, et al. A Phase II, randomized, double-blind, multicenter, based on standard therapy, placebo-controlled study of the efficacy and safety of recombinant human neuregulin-1 in patients with chronic heart failure. J Am Coll Cardiol
9. Jabbour A, Hayward CS, Keogh AM, Kotlyar E, McCrohon JA, England JF, et al. Parenteral administration of recombinant human neuregulin-1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses. Eur J Heart Fail
10. Buonanno A, Fischbach GD. Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol
11. Thompson M, Lauderdale S, Webster MJ, Chong VZ, McClintock B, Saunders R, Weickert CS. Widespread expression of ErbB2, ErbB3 and ErbB4 in nonhuman primate brain. Brain Res
12. Yao JJ, Sun J, Zhao QR, Wang CY, Mei YA. Neuregulin-1/ErbB4 signaling regulates Kv4.2-mediated transient outward K+ current through the Akt/mTOR pathway. Am J Physiol Cell Physiol
13. Matsukawa R, Hirooka Y, Nishihara M, Ito K, Sunagawa K. Neuregulin-1/ErbB signaling in rostral ventrolateral medulla is involved in blood pressure regulation as an antihypertensive system. J Hypertens
14. Matsukawa R, Hirooka Y, Ito K, Honda N, Sunagawa K. Central neuregulin-1/ErbB signaling modulates cardiac function via sympathetic activity in pressure overload-induced heart failure. J Hypertens
15. Kapusta DR, Pascale CL, Kuwabara JT, Wainford RD. Central nervous system Galphai2-subunit proteins maintain salt resistance via a renal nerve-dependent sympathoinhibitory pathway. Hypertension
16. Wainford RD, Kapusta DR. Functional selectivity of central Galpha-subunit proteins in mediating the cardiovascular and renal excretory responses evoked by central alpha(2)-adrenoceptor activation in vivo. Br J Pharmacol
17. Wainford RD, Pascale CL, Kuwabara JT. Brain Galphai2-subunit protein-gated pathways are required to mediate the centrally evoked sympathoinhibitory mechanisms activated to maintain sodium homeostasis. J Hypertens
18. Hirooka Y, Kishi T, Ito K, Sunagawa K. Potential clinical application of recently discovered brain mechanisms involved in hypertension. Hypertension