HB-EGF induces cardiomyocyte hypertrophy via an ERK5-MEF2A-COX2 signaling pathway.
Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family that binds to and activates the EGF receptor. Transactivated by angiotensin II, ET-1, and various growth factors in cardiomyocytes, HB-EGF is known to induce cardiac hypertrophy via the PI3K-Akt, MAP kinase, and JAK-STAT pathways. However, little is known about the potential involvement of the ERK5 pathway in HB-EGF-induced cardiac hypertrophy. In the present report, we identify and characterize a novel MEK5-ERK5 pathway that is involved in HB-EGF-induced cardiomyocyte hypertrophy. HB-EGF (10ng/ml) significantly increased [(3)H]-leucine incorporation and atrial natriuretic factor (ANF) mRNA expression in H9c2 cells. In addition, HB-EGF activated a MEK5-ERK5 pathway. Pretreatment with the EGFR inhibitor AG1478 attenuated the activation of ERK5. Blockade of MEK5-ERK5 signaling using MEK5 siRNA reduced the ability of HB-EGF to increase cell size and the expression of ANF mRNA, suggesting the involvement of an EGFR-ERK5 pathway in HB-EGF-induced cardiomyocyte hypertrophy. We further analyzed cyclooxygenase-2 (COX-2). HB-EGF enhanced the expression of COX-2, a response mediated by MEK5-ERK5 signaling, while the COX-2 inhibitor rofecoxib attenuated HB-EGF-induced ANF mRNA expression, suggesting that COX-2 is also associated with HB-EGF-induced cardiomyocyte hypertrophy. It has been known that ERK5 activates the myocyte enhancer factor (MEF) 2 family of transcription factor, we next tested whether activation of MEF2A contributes to HB-EGF-induced COX-2 expression. Inhibition of MEF2A using siRNA attenuated HB-EGF-induced COX-2, ANF expression and cell size. In conclusion, HB-EGF induces cardiomyocyte hypertrophy through an EGFR-ERK5-MEF2A-COX-2 pathway. Our findings will help us to better understand the molecular mechanisms behind HB-EGF-induced cardiomyocyte hypertrophy.
Division of Cardiovascular and Rare Diseases, Center for Biomedical Sciences, National Institute of Health, Seoul, Korea.
Kuy-Sook
KS
Lee
Jin-Hee
JH
Park
Hyun-Joung
HJ
Lim
Hyun-Young
HY
Park
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D049108:Cell Enlargement; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology*; D026161:MADS Domain Proteins / Q000378:metabolism*; D048671:MAP Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic
C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578037:MEF2A protein, rat; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D066246:ErbB Receptors; D048054:Mitogen-Activated Protein Kinase 7; D048671:MAP Kinase Kinase 5; C482565:Map2k5 protein, rat