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.