[The role of HB-EGF in angiotensin II--signaling]

G-protein coupled receptor agonists such as phenylephrine, angiotensin II, and endothelin-1 are well-known inducers of cardiac hypertrophy. We demonstrated that both metalloproteinase inhibitor and HB-EGF neutralizing antibody abrogated the trans-activation of the receptor for epidermal growth factor by phenylephrine, angiotensin II, or endothelin-1 in cultured rat neonatal cardiomyocytes. We cloned ADAM12(a disintegrin and metalloprotease 12) as a specific enzyme to cleave HB-EGF in cardiomyocytes. We also showed that a metalloproteinase inhibitor attenuates cardiac hypertrophy in aortic banding mice. These data suggest that release of HB-EGF by ADAM12 plays a crucial role in hypertrophic signaling of cardiomyocytes, and that inhibition of HB-EGF shedding could be a potent therapeutic strategy for cardiac hypertrophy.