A central role of EGF receptor transactivation in angiotensin II -induced cardiac hypertrophy.
In addition to their physiological roles in the cardiovascular system (CVS), G-protein-coupled receptor (GPCR) agonists such as noradrenaline, endothelin-1 and angiotensin II (Ang II) are known to be involved in the development of cardiac hypertrophy. Recent studies using targeted overexpression of the angiotensin AT(1) receptor in cardiomyocytes suggest that Ang II can directly promote the growth of cardiomyocytes via transactivation of the epidermal growth factor (EGF) receptor and subsequent activation of mitogen-activated protein kinases (MAPKs). This process is mediated by the production of heparin-binding EGF (HB-EGF) by metalloproteases. Blockade of the generation of HB-EGF by metalloprotease inhibitors, or abrogation of EGF receptor kinase activity by selective pharmacological inhibitors or antisense oligonucleotides, protects against Ang II-mediated cardiac hypertrophy. These approaches offer a potential therapeutic strategy to prevent cardiac remodeling and hypertrophy, and possibly prevent progression to heart failure.
Shah
Bukhtiar H
BH
Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4510, USA. shahb@mail.nih.gov
Catt
Kevin J
KJ
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*
D000804:Angiotensin II; D066246:ErbB Receptors