Pharmacological role of HB-EGF shedding by angiotensin II in cardiomyocytes

Abstract

Angiotenesin II (AGII) is known to induce cardiac hypertrophy. Prolonged hypertrophy leads to reduced cardiac performance. The cardiac protective effect of AGII antagonist implies the potential role of AGII in the transition from cardiac hypertrophy to heart failure. Here we report a new mechanism of HB-EGF mediated cardiac hypertrophy induced by AGII. HB-EGF is a EGF family growth factor synthesized as the membrane anchored form and released by protease cleavage to activate its receptor. In cultured cardiomyocytes, AGII induced the transactivation of EGF receptor, which was blocked by metalloproteinase inhibitor KBR-7785 and HB-EGF-neurtralizing antibody # 19. Both KBR-7785 and # 19 attenuated the cardiac hypertrophy by AGII in vitro and in vivo. Thus we conclude that AGII activates metalloproteinase and sheds HB-EGF. Released HB-EGF bound to EGF receptor, leading to the cardiac hypertrophy. Recently, similar transactivation of EGF receptor by a GPCR agonist has been reported in various organs, indicating that EGF receptor transactivation by HB-EGF might play the general role of pharmacological reaction by AGII.