Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 2002;105:e9

This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shizukuda, Y.
Right arrow Articles by Shibasaki, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shizukuda, Y.
Right arrow Articles by Shibasaki, F.
Related Collections
Right arrow Apoptosis
Right arrow Cell biology/structural biology
Right arrow Cell signalling/signal transduction
Right arrow Gene expression
Right arrow Heart failure - basic studies
Right arrow Information technology

(Circulation. 2002;105:e9.)
© 2002 American Heart Association, Inc.

Correspondence

Isoprotrenol Activates Extracellular Signal-Regulated Protein Kinases in Cardiomyocytes Through Calcineurin

Yukitaka Shizukuda, MD PhD, FACC; Peter M. Buttrick, MD FACC

Section of Cardiology, University of Illinois at Chicago

To the Editor:

Zou et al1 reported recently that isoproterenol activates extracellular signal-regulated protein kinases (ERK) in cardiomyocytes through calcineurin. The results mediated by ß-adrenergic receptors (ß-AR) were convincing in neonatal cardiomyocytes but might not be applicable to adult cardiomyocytes, which undergo pathological hypertrophy. Communal et al2 demonstrated that ERK is not activated by isoproterenol using adult rat ventricular myocytes kept in culture for 16 hours. Recently, we made a similar observation using adult cardiomyocytes cultured for 48 hours.3 It is clear that signal transduction mediated by ß-AR and Gs and Gi coupling to ß-AR subtypes differs between adult and neonatal cardiomyocytes. The dosages of isoproterenol used to induce hypertrophy in neonatal cardiac myocytes in the study of Zou et al induces cardiomyocyte death by apoptosis rather than hypertrophy in adult cardiomyocytes.4,5 Although Zou et al reported similar activation of ERK by ß-AR stimulation in whole hearts, hypertrophy induced by in vivo administration of isoproterenol to transgenic mice is much more complicated than that seen in cultured myocytes because of systemic neurohormonal changes induced by ß-AR and contamination by non-myocyte cells. Therefore, further investigation is needed to verify that the cross-talk discussed in cultured neonatal cardiomyocytes induced by ß-AR is responsible for the hypertrophy seen in adult cardiomyocytes.

References

  1. Zou Y, Yao A, Zhu W, et al. Isoproterenol activates extracellular signal-regulated protein kinases in cardiomyocytes through calcineurin. Circulation. 2001; 104: 102–108.[Abstract/Free Full Text]
  2. Communal C, Colucci WS, Singh K. p38 Mitogen-activated protein kinase pathway protects adult rat ventricular myocytes against ß-adrenergic receptor-stimulated apoptosis: evidence for Gi-dependent activation. J Biol Chem. 2000; 275: 19395–19400.[Abstract/Free Full Text]
  3. Shizukuda Y, Naya T, Pham TA, et al. Protein kinase C{epsilon} modulates apoptosis induced by ß-adrenertic stimulation in adult cardiac myocytes: role of ß2-adrenergic receptor dependent ERK activation. J Am Coll Cardiol. 2001; 37: 160A.Abstract.
  4. Communal C, Singh K, Pimentel DR, et al. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the ß-adrenergic pathway. Circulation. 1998; 98: 1329–1334.[Abstract/Free Full Text]
  5. Zaugg M, Xu W, Lucchinetti E, et al. ß-Adrenergic receptor subtypes differentially affect apoptosis in adult rat ventricular myocytes. Circulation. 2000; 102: 344–350.[Abstract/Free Full Text]
 

Response

Y. Zou, MD PhD; I. Komuro, MD PhD

Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine

A. Yao, MD PhD; W. Zhu, MD PhD; S. Kudoh, MD PhD; Y. Hiroi, MD PhD; M. Shimoyama, MD PhD; H. Uozumi, MD PhD; T. Takahashi, MD PhD; R. Nagai, MD PhD; Y. Yazaki, MD PhD

Department of Cardiovascular Medicine University of Tokyo Graduate School of Medicine Tokyo, Japan

O. Kohmoto, MD PhD

Department of Medicine II, Saitama Medical School, Saitama, Japan

F. Shibasaki, MD PhD

Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

We thank Drs Shizukuda and Buttrick for their interest in our paper,1 but we disagree with some of their arguments and interpretations. Although there should be differences in various aspects between neonatal and adult cardiomyocytes, many studies have demonstrated that stimulation of ß-adrenergic receptors induces activation of extracellular signal-regulated protein kinases (ERK) and hypertrophy in both cultured neonatal1,2 and adult3,4 cardiomyocytes. Communal et al3 also reported that ERK1/2 activity was increased 2.6±0.4-fold at 60 minutes by ß-adrenergic receptor activation. Stimulation of ß-adrenergic receptors has 2 diverse effects on both neonatal and adult cardiomyocytes: (1) induction of hypertrophy2,4 and (2) apoptosis.1,3,5 Isoproterenol (1~10 µmol/L) induces apoptosis as well as hypertrophy in neonatal1,2,5 and adult4 cardiomyocytes. Activated calcineurin may be involved in isoproterenol-induced apoptosis5 and hypertrophy1 possibly by dephosphorylating Bad and by activating NFAT-3, respectively. ß-Adrenergic receptor activation might induce in vivo cardiac hypertrophy by cross-talk with many other neurohumoral factors as well as by an increase in hemodynamic overload. However, results obtained so far from cultured cardiomyocytes indicate that there is no obvious difference between neonatal and adult cardiomyocytes in terms of the effects of ß-adrenergic stimulation on ERK, hypertrophy, and apoptosis.

References

  1. Zou Y, Yao A, Zhu W, et al. Isoproterenol activates extracellular signal-regulated protein kinases in cardiomyocytes through calcineurin. Circulation. 2001; 104: 102–108.
  2. Zou Y, Komuro I, Yamazaki T, et al. Both Gs and Gi proteins are critically involved in isoproterenol-induced cardiomyocyte hypertrophy. J Biol Chem. 1999; 274: 9760–9770.[Abstract/Free Full Text]
  3. Communal C, Colucci WS, Singh K. p38 Mitogen-activated protein kinase pathway protects adult rat ventricular myocytes against ß-adrenergic receptor-stimulated apoptosis. J Biol Chem. 2000; 275: 19395–19400.
  4. Simm A, Schluter KD, Diez C, et al. Activation of p70S6 kinase by ß-adrenoceptor agonists on adulat cardiomyocytes. J Mol Cell Cardiol. 1998; 30: 2059–2067.[CrossRef][Medline] [Order article via Infotrieve]
  5. Saito S, Hiroi Y, Zou Y, et al. ß-Adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes. J Biol Chem. 2000; 275: 34528–34533.[Abstract/Free Full Text]




This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shizukuda, Y.
Right arrow Articles by Shibasaki, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shizukuda, Y.
Right arrow Articles by Shibasaki, F.
Related Collections
Right arrow Apoptosis
Right arrow Cell biology/structural biology
Right arrow Cell signalling/signal transduction
Right arrow Gene expression
Right arrow Heart failure - basic studies
Right arrow Information technology

Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2002 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.