TY - JOUR
T1 - Multiple signalling pathways underlie the protective effect of levosimendan in cardiac myocytes
AU - Markou, Thomais
AU - Makridou, Zoe
AU - Galatou, Eleftheria
AU - Lazou, Antigone
PY - 2011/9/30
Y1 - 2011/9/30
N2 - Levosimendan is a cardiovascular drug for the treatment of acute and decompensated heart failure. The current weight of evidence on the cardioprotective effects of levosimendan originates from whole heart models and there is no information on the mechanism whereby signalling pathways are activated. In the present study, we investigated the effect of levosimendan on ischaemia/reperfusion injury and the underlying mechanism in cardiac myocytes. Pretreatment with levosimendan reversed the effects of ischaemia and ischaemia/reperfusion on cell viability and enhanced phosphorylation of Akt, p38-mitogen activated protein kinase (MAPK) and extracellular signal-regulated kinases 1/2 (ERK1/2). Inhibitors of these kinases and the blocker of the mitochondrial K ATP channels, 5-hydroxydecanoate, completely abolished the protection afforded by levosimendan. Levosimendan stimulated the phosphorylation of Akt, ERK1/2 and p38-MAPK with different kinetics and the activation of these pathways was dependent on the opening of the mitochondrial K ATP channels and the production of oxygen free radicals. The levosimendan-induced phosphorylation of ERK1/2 and Akt was reduced by inhibitors of epidermal growth factor receptor and Src. On the other hand, inhibition of the protein kinase A (PKA) pathway reduced phosphorylation of p38-MAPK. Furthermore, p38-MAPK was activated when a phosphodiesterase inhibitor or a selective PKA activator was used. Overall, our results suggest that levosimendan regulates the wiring of the natural salvaging pathways to execute the prosurvival signals. This network includes Akt, ERK1/2 and p38-MAPK. Opening of mitochondrial K ATP channels and the subsequent production of oxygen free radicals, the epidermal growth factor receptor/Src, and the cAMP/PKA pathways seem to mediate this response.
AB - Levosimendan is a cardiovascular drug for the treatment of acute and decompensated heart failure. The current weight of evidence on the cardioprotective effects of levosimendan originates from whole heart models and there is no information on the mechanism whereby signalling pathways are activated. In the present study, we investigated the effect of levosimendan on ischaemia/reperfusion injury and the underlying mechanism in cardiac myocytes. Pretreatment with levosimendan reversed the effects of ischaemia and ischaemia/reperfusion on cell viability and enhanced phosphorylation of Akt, p38-mitogen activated protein kinase (MAPK) and extracellular signal-regulated kinases 1/2 (ERK1/2). Inhibitors of these kinases and the blocker of the mitochondrial K ATP channels, 5-hydroxydecanoate, completely abolished the protection afforded by levosimendan. Levosimendan stimulated the phosphorylation of Akt, ERK1/2 and p38-MAPK with different kinetics and the activation of these pathways was dependent on the opening of the mitochondrial K ATP channels and the production of oxygen free radicals. The levosimendan-induced phosphorylation of ERK1/2 and Akt was reduced by inhibitors of epidermal growth factor receptor and Src. On the other hand, inhibition of the protein kinase A (PKA) pathway reduced phosphorylation of p38-MAPK. Furthermore, p38-MAPK was activated when a phosphodiesterase inhibitor or a selective PKA activator was used. Overall, our results suggest that levosimendan regulates the wiring of the natural salvaging pathways to execute the prosurvival signals. This network includes Akt, ERK1/2 and p38-MAPK. Opening of mitochondrial K ATP channels and the subsequent production of oxygen free radicals, the epidermal growth factor receptor/Src, and the cAMP/PKA pathways seem to mediate this response.
KW - Akt
KW - Cardiac myocyte
KW - Ischaemia
KW - Levosimendan
KW - MAPK
KW - Signalling pathway
UR - http://www.scopus.com/inward/record.url?scp=80052029553&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2011.05.078
DO - 10.1016/j.ejphar.2011.05.078
M3 - Article
C2 - 21664904
AN - SCOPUS:80052029553
SN - 0014-2999
VL - 667
SP - 298
EP - 305
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -