Functionally opposing roles of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in the regulation of cardiac contractility.
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).


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.
Szokodi
István
I
Institute of Biomedicine, Department of Pharmacology and Toxicology, Faculty of Medicine, University of Oulu, PO Box 5000, 90014 University of Oulu, Finland.
Kerkelä
Risto
R
Kubin
Anna-Maria
AM
Sármán
Balázs
B
Pikkarainen
Sampsa
S
Kónyi
Attila
A
Horváth
Iván G
IG
Papp
Lajos
L
Tóth
Miklós
M
Skoumal
Réka
R
Ruskoaho
Heikki
H
D000818:Animals; D019332:Endothelin-1 / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D019332:Endothelin-1; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases