Cross-talk between bone morphogenetic protein 2 and leukemia inhibitory factor through ERK 1/2 and Smad1 in protection against doxorubicin-induced injury of cardiomyocytes.
The survival of cardiomyocytes is regulated by growth factors and cytokines such as bone morphogenetic protein (BMP) 2 and leukemia inhibitory factor (LIF). BMP2 and LIF induce distinct signal transduction pathways that each activate a different transcription factor [Smad1 and signal transducing activating transcriptional factor (Stat) 3, respectively] and common signal pathway [mitogen-activated protein kinase (MAPK)]. We previously demonstrated that BMP2 and LIF protect cardiomyocytes via Smad1 and STAT3 signaling pathways, respectively. On the other hand, these signals are known to act in synergy via synergistic integration of signaling pathways. Here, we examined interaction between BMP2 and LIF in primary cultured neonatal rat cardiomyocytes. LIF sustained phosphorylation/activation of Smad1 by BMP2. The role of extracellular signal-regulated kinase (ERK) 1/2 cascade activated by LIF was highlighted by the use of a MAPK/ERK kinase (MEK) 1/2 inhibitor, U0126, or overexpression of dominant-negative form of MEK1 that abolished sustained phosphorylation of Smad1 and cell survival effect induced by co-stimulation of LIF with BMP2, while BMP2 alone did not activate ERK1/2. Conversely, overexpression of the constitutive-active form of MEK1 increased BMP2-induced phosphoration of Smad1 without additional LIF. Moreover, BMP2 and LIF synergistically induced bcl-xL mRNA in doxorubicin (DOX)-injured cardiomyocytes. These findings suggest that the ERK1/2 pathway downstream of LIF is involved in sustained phosphorylation/activation of Smad1 by BMP2 and provide a possible mechanism for cooperation between intracellular signals activated by LIF and BMP2 in protection against DOX-induced injury of cardiomyocytes.
Izumi
Masahiro
M
Department of Cardiology, Osaka Medical Center for Cancer and Cardiovascular Disease, 1-3-3, Nakamichi, Higashinari-ku, Osaka, Osaka 537-8511, Japan.
Masaki
Mitsuru
M
Hiramoto
Yoshimune
Y
Sugiyama
Shoko
S
Kuroda
Tadashi
T
Terai
Kazuo
K
Hori
Masatsugu
M
Kawase
Ichiro
I
Hirota
Hisao
H
D000256:Adenoviridae; D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051898:Smad1 Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
D000903:Antibiotics, Antineoplastic; C494811:BCL2L1 protein, human; C525718:BMP2 protein, human; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D053605:Leukemia Inhibitory Factor; D012333:RNA, Messenger; D051898:Smad1 Protein; C497400:Smad1 protein, rat; D016212:Transforming Growth Factor beta; D051020:bcl-X Protein; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human