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(Circulation. 2005;111:e175.)
© 2005 American Heart Association, Inc.

Correspondence

Letter Regarding Article by Okoshi et al, "Neuregulins Regulate Cardiac Parasympathetic Activity: Muscarinic Modulation of ß-Adrenergic Activity in Myocytes From Mice With Neuregulin-1 Gene Deletion"

Katrien Lemmens, MD; Vincent F.M. Segers, MD; Gilles W. De Keulenaer, MD, PhD

Laboratory of Physiology, University of Antwerp, Antwerp, Belgium, gilles.dekeulenaer{at}ua.ac.be

To the Editor:

Okoshi and colleagues¹ studied the modulatory role of neuregulin-1 on parasympathetic activity in the heart. This interesting study on isolated cardiomyocytes showed that heterozygous gene deletion of neuregulin-1 abrogated the inhibitory activity of the muscarinic cholinergic system on ß-adrenergic signaling. Because protein levels of M₂ muscarinic receptors and G protein subunits were unchanged in neuregulin-1–deficient cardiomyocytes, the authors proposed that neuregulins support normal parasympathetic modulation of excess ß-adrenergic stimulation of the heart.

In a recent article in Circulation,² we reported that exogenously administrated neuregulin-1 attenuated ß-adrenergic responses of isolated papillary muscles in the absence of exogenous muscarinic activation. Our data suggested that neuregulin-1 also had direct antiadrenergic effects, rather than a mere supporting role in the antiadrenergic effects of the parasympathetic system. To further reinforce our conclusion, after reading the article by Okoshi et al, we repeated our experiments in papillary muscles pretreated with atropine to inhibit background muscarinic activity from parasympathetic nerve endings. The results of these experiments indicated that the antiadrenergic effects of neuregulin-1 disappeared when muscarinic receptors were blocked. Our findings and those by Okoshi et al seem to be consistent as they both reveal a unique and powerful interaction between the parasympathetic system and neuregulin signaling. More specifically, it appears that both components rely on cooperativity for an inhibitory effect on the adrenergic system.

One aspect of the article by Okoshi et al, however, is unclear to us. The authors made their observations of neuregulin-1 gene deletion in isolated cardiomyocytes, whereas neuregulin-1 is an endothelial factor, which according to our (unpublished) and others’ observations is not or is only minimally expressed in cardiomyocytes.³ How do the authors explain this? Also, did the authors try to rescue the carbachol-resistant NRG-1^+/– phenotype with exogenous neuregulin-1?

	References

Top References References

 

1. Okoshi K, Nakayama M, Yan X, Okoshi MP, Schuldt AJ, Marchionni MA, Lorell BH. Neuregulins regulate cardiac parasympathetic activity: muscarinic modulation of ß-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion. Circulation. 2004; 110: 713–717.[Abstract/Free Full Text]
   
2. Lemmens K, Fransen P, Sys SU, Brutsaert DL, De Keulenaer GW. Neuregulin-1 induces a negative inotropic effect in cardiac muscle: role of nitric oxide synthase. Circulation. 2004; 109: 324–326.[Abstract/Free Full Text]
   
3. Garratt AN, Ozcelik C, Birchmeier C. ErbB2 pathways in heart and neural diseases. Trends Cardiovasc Med. 2003; 13: 80–86.[CrossRef][Medline] [Order article via Infotrieve]
   

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Response

Katashi Okoshi, MD; Masaharu Nakayama, MD; Xinhua Yan, MD; Marina P. Okoshi, MD; Adam J.T. Schuldt, BA; Beverly H. Lorell, MD

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass

Mark A. Marchionni, PhD

NRG Biotech, Arlington, Mass

We appreciate the interest of Dr Lemmens and colleagues in our work.¹ The study by Lemmens et al² is important because it suggests that neuregulin-1 (NRG-1) also has a direct antiadrenergic effect. We agree that, taken together, the observations from both studies strongly suggest that the capability of the heart to counterbalance ß-adrenergic activity is impaired when the neuregulin-erbB pathway is suppressed.

With regard to the questions raised by the investigators, available data indicate that neuregulin-1 expressed in the endocardium and microvascular endothelium mediates paracrine signaling to neighboring cardiomyocytes.³ The downstream components of such signaling are likely to include nitric oxide synthase but are as yet incompletely understood. It is likely and plausible, however, that in the heterozygote NRG-1^+/– mouse, this altered paracrine activity results in chronic changes in gene expression that are involved in the cardiac parasympathetic system signaling pathway. Such changes in gene expression would be expected to persist in the freshly isolated cardiomyocytes from the heterozygote NRG-1^+/– mouse, thus leading to the observed phenotype. In our study, we did not try to rescue the carbachol-resistant NRG-1^+/– phenotype with exogenous recombinant neuregulin-1. This is a fruitful line of future investigation in both in vivo and in vitro experiments.

	References

Top References References

 

1. Okoshi K, Nakayama M, Yan X, Okoshi MP, Schuldt AJ, Marchionni MA, Lorell BH. Neuregulins regulate cardiac parasympathic activity: muscarinic modulation of ß-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion. Circulation. 2004; 110: 713–717.[Abstract/Free Full Text]
   
2. Lemmens K, Fransen P, Sys SU, Brutsaert DL, De Keulenaer GW. Neuregulin-1 induces a negative inotropic effect in cardiac muscle: role of nitric oxide synthase. Circulation. 2004; 109: 324–326.[Abstract/Free Full Text]
   
3. Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res. 2003; 284: 14–30.[CrossRef][Medline] [Order article via Infotrieve]
   

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