ADAM17 mediates epidermal growth factor receptor transactivation and vascular smooth muscle cell hypertrophy induced by angiotensin II.
BACKGROUND
Angiotensin II (Ang II) promotes growth of vascular smooth muscle cells (VSMCs) via epidermal growth factor (EGF) receptor (EGFR) transactivation mediated through a metalloprotease-dependent shedding of heparin-binding EGF-like growth factor (HB-EGF). However, the identity of the metalloprotease responsible for this process remains unknown.


RESULTS
To identify the metalloprotease required for Ang II-induced EGFR transactivation, primary cultured aortic VSMCs were infected with retrovirus encoding dominant negative (dn) mutant of ADAM10 or ADAM17. EGFR transactivation induced by Ang II was inhibited in VSMCs infected with dnADAM17 retrovirus but not with dnADAM10 retrovirus. However, Ang II comparably stimulated intracellular Ca2+ elevation and JAK2 tyrosine phosphorylation in these VSMCs. In addition, dnADAM17 inhibited HB-EGF shedding induced by Ang II in A10 VSMCs expressing the AT1 receptor. Moreover, Ang II enhanced protein synthesis and cell volume in VSMCs infected with control retrovirus, but not in VSMCs infected with dnADAM17 retrovirus.


CONCLUSIONS
ADAM17 activated by the AT1 receptor is responsible for EGFR transactivation and subsequent protein synthesis in VSMCs. These findings demonstrate a previously missing molecular mechanism by which Ang II promotes vascular remodeling.
Ohtsu
Haruhiko
H
Cardiovascular Research Center, Temple University School of Medicine, 3420 N. Broad St, Philadelphia, PA 19140, USA.
Dempsey
Peter J
PJ
Frank
Gerald D
GD
Brailoiu
Eugen
E
Higuchi
Sadaharu
S
Suzuki
Hiroyuki
H
Nakashima
Hidekatsu
H
Eguchi
Kunie
K
Eguchi
Satoru
S
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics*; D005799:Genes, Dominant; D006984:Hypertrophy; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology*; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection
D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat