Skip to main content
ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #146650
Title: HEPATOCYTE GROWTH FACTOR INDUCES GATA-4 PHOSPHORYLATION IN CARDIAC MUSCLE CELLS

Author
item KITTA, KAZUMI - HNRCA
item DAY, REGINA - NEMC
item KIM, YURI - HNRCA
item EVANS, TODD - ALBERT EINSTEIN COLL MED
item SUZUKI, YUICHIRO - HNRCA

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/14/2002
Publication Date: 2/14/2003
Citation: KITTA, K., DAY, R., KIM, Y., EVANS, T., SUZUKI, Y.J. HEPATOCYTE GROWTH FACTOR INDUCES GATA-4 PHOSPHORYLATION IN CARDIAC MUSCLE CELLS. JOURNAL OF BIOLOGICAL CHEMISTRY. 278(7):4705-12,2003.

Interpretive Summary: The heart is subjected to stress during such conditions as the heart attack. To reduce the heart damage, our bodies have defense mechanisms. The present study investigated how a protein called hepatocyte growth factor (HGF) may protect the heart against stress. We found that stress-induced death of heart muscle cells is protected by HGF by a cascade of events involving various cellular molecules. These results will be useful to design therapeutic and dietary strategies for protecting the heart during such conditions as heart attack and cancer chemotherapy-induced heart damage.

Technical Abstract: 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. Since 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 which 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 inhibitorsor 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-xL, 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-xL. 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.