Hepatocyte growth factor induces GATA-4 phosphorylation and cell survival in cardiac muscle cells.
Hepatocyte growth factor (HGF) is released in response to myocardial infarction and may play a role in regulating cardiac remodeling. Recently, HGF was found to inhibit the apoptosis of cardiac muscle cells. Because GATA-4 can induce cell survival, the effects of HGF on GATA-4 activity were investigated. Treatment of HL-1 cells or primary adult rat cardiac myocytes with HGF, at concentrations that can be detected in the human serum after myocardial infarction, rapidly enhances GATA-4 DNA-binding activity. The enhanced DNA-binding activity is associated with the phosphorylation of GATA-4. HGF-induced phosphorylation and activation of GATA-4 is abolished by MEK inhibitors or the mutation of the ERK phosphorylation site (S105A), suggesting that HGF activates GATA-4 via MEK-ERK pathway-dependent phosphorylation. HGF enhances the expression of anti-apoptotic Bcl-x(L), and this is blocked by dominant negative mutants of MEK or GATA-4. Forced expression of wild-type GATA-4, but not the GATA-4 mutant (S105A) increases the expression of Bcl-x(L). Furthermore, expression of the GATA-4 mutant (S105A) suppresses HGF-mediated protection of cells against daunorubicin-induced apoptosis. These results demonstrate that HGF protects cardiac muscle cells against apoptosis via a signaling pathway involving MEK/ERK-dependent phosphorylation of GATA-4.
Kitta
Kazumi
K
Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts 02111, USA.
Day
Regina M
RM
Kim
Yuri
Y
Torregroza
Ingrid
I
Evans
Todd
T
Suzuki
Yuichiro J
YJ
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050991:GATA4 Transcription Factor; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor