This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 118/16/1651    most recent CIRCULATIONAHA.107.758623v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Szokodi, I. Articles by Ruskoaho, H. Search for Related Content PubMed PubMed Citation Articles by Szokodi, I. Articles by Ruskoaho, H. Related Collections Contractile function Cell signalling/signal transduction Related Article

(Circulation. 2008;118:1651-1658.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Functionally Opposing Roles of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase in the Regulation of Cardiac Contractility

István Szokodi, MD, PhD^*; Risto Kerkelä, MD, PhD^*; Anna-Maria Kubin, MD; Balázs Sármán, MD, PhD; Sampsa Pikkarainen, MD, PhD; Attila Kónyi, MD; Iván G. Horváth, MD, PhD; Lajos Papp, MD, PhD; Miklós Tóth, MD, PhD; Réka Skoumal, PhD; Heikki Ruskoaho, MD, PhD

From the Institute of Biomedicine, Department of Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, Oulu, Finland (I.S., R.K., A.-M.K., S.P., R.S., H.R.); Heart Institute, Medical School, University of Pécs, Pécs, Hungary (I.S., A.K., I.G.H., L.P.); Center for Translational Medicine, Jefferson Medical College, Philadelphia, Pa (R.K.); and Szentágothai János Knowledge Centre, Budapest, Hungary (B.S., M.T., R.S.).

Correspondence to Heikki Ruskoaho, MD, PhD, Institute of Biomedicine, Department of Pharmacology and Toxicology, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 University of Oulu, Finland. E-mail heikki.ruskoaho{at}oulu.fi

Received March 12, 2006; accepted August 4, 2008.

Background— Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38-MAPK) have been shown to regulate various cellular processes, including cell growth, proliferation, and apoptosis in the heart. However, the function of these signaling pathways in the control of cardiac contractility is unclear. Here, we characterized the contribution of ERK1/2 and p38-MAPK to the inotropic effect of endothelin-1 (ET-1).

Methods and Results— In isolated perfused rat hearts, infusion of ET-1 (1 nmol/L) for 10 minutes increased contractility and phosphorylation of ERK1/2 and their downstream target p90 ribosomal S6 kinase (p90RSK). Suppression of ERK1/2 activation prevented p90RSK phosphorylation and attenuated the inotropic effect of ET-1. Pharmacological inhibition of epidermal growth factor receptor kinase activity abolished ET-1–induced epidermal growth factor receptor transactivation and ERK1/2 and p90RSK phosphorylation and reduced ET-1–mediated inotropic response. Moreover, inhibition of the p90RSK target Na⁺-H⁺ exchanger 1 attenuated the inotropic effect of ET-1. In contrast to ERK1/2 signaling, suppression of p38-MAPK activity further augmented ET-1–enhanced contractility, which was accompanied by increased phosphorylation of phospholamban at Ser-16.

Conclusions— MAPKs play opposing roles in the regulation of cardiac contractility in that the ERK1/2-mediated positive inotropic response to ET-1 is counterbalanced by simultaneous activation of p38-MAPK. Hence, selective activation of ERK1/2 signaling and inhibition of p38-MAPK signaling may represent novel means to support cardiac function in disease.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 118: 1605-1606. [Extract] [Full Text]

This article has been cited by other articles:

				E. Calderon-Sanchez, C. Delgado, G. Ruiz-Hurtado, A. Dominguez-Rodriguez, V. Cachofeiro, M. Rodriguez-Moyano, A. M. Gomez, A. Ordonez, and T. Smani Urocortin induces positive inotropic effect in rat heart Cardiovasc Res, September 1, 2009; 83(4): 717 - 725. [Abstract] [Full Text] [PDF]