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

Abstract

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 ϩ -H ϩ 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

Key roles of endothelin-1 and p38 MAPK in the regulation of atrial stretch response

“…We found that stretch-induced increase in cardiac contractility in isolated rat atria was enhanced by inhibition of p38 MAPK. There is already convincing data indicating a negative role for the p38 MAPK mediating the inotropic effect in ventricular cardiomyocytes both in vivo and in vitro (27,28,44) (for review, see Ref. 22).…”

“…In addition, AF is also associated with increased atrial mRNA levels of endothelin-1 (ET-1) (31). In the left ventricle, ET-1 augments left ventricular contractile function and activates hypertrophic signaling pathways (43,44). In fact, the signaling mechanisms regulating hypertrophic response in ventricular cardiomyocytes have been studied extensively, but signaling mechanisms involved in stress response in atrial myocardium are not well understood.…”

Reaktívoxigén-származékok szerepe a szívműködés szabályozásában

“…Mechanizmusát tekintve, a β-AR-választól eltérően, az ET-1 elsősorban a miofi lamentumok Ca 2+ -érzékenységét fokozva képes növelni a szívizom-össze-húzódások erejét. A peptid inotrop hatását az ET A -receptorok közvetítik az epidermalis növekedési faktor receptor (EGFR) extracelluláris szignál által regulált kináz 1/2 (ERK1/2)−p90 riboszomális S6-kináz−Na + / H + cseremechanizmus jelátviteli út aktivációja révén [17].…”

“…Eredményeink szerint az ERK1/2 aktivációja, amely alapvető szerepet tölt be az ET-1 pozitív inotrop hatásá-nak közvetítésében [17], döntően ROS-érzékeny, mivel az N-acetil-cisztein és az apocynin is szignifi kánsan csök-kentette az ET-1 indukálta ERK1/2-foszforilációt [14]. Korábban kimutattuk, hogy az ET-1 az EGFR transzaktiváció révén váltja ki az ERK1/2 aktivációját [17].…”

“…Korábban kimutattuk, hogy az ET-1 az EGFR transzaktiváció révén váltja ki az ERK1/2 aktivációját [17]. A ROS-termelődés fokozódása inaktiválhatja a proteintirozin foszfatázokat és ily módon emelkedhet az EGFR tirozinfoszforilációja.…”