title: Caveolin-1 negatively regulates a metalloprotease-dependent epidermal growth factor receptor transactivation by angiotensin II.
abstract: A metalloprotease, ADAM17, mediates the generation of mature ligands for the epidermal growth factor receptor (EGFR). This is the key signaling step by which angiotensin II (AngII) induces EGFR transactivation leading to hypertrophy and migration of vascular smooth muscle cells (VSMCs). However, the regulatory mechanism of ADAM17 activity remains largely unclear. Here we hypothesized that caveolin-1 (Cav1), the major structural protein of a caveolae, a membrane microdomain, is involved in the regulation of ADAM17. In cultured VSMCs, infection of adenovirus encoding Cav1 markedly inhibited AngII-induced EGFR ligand shedding, EGFR transactivation, ERK activation, hypertrophy and migration, but not intracellular Ca(2+) elevation. Methyl-β-cyclodextrin and filipin, reagents that disrupt raft structure, both stimulated an EGFR ligand shedding and EGFR transactivation in VSMCs. In addition, non-detergent sucrose gradient membrane fractionations revealed that ADAM17 cofractionated with Cav1 in lipid rafts. These results suggest that lipid rafts and perhaps caveolae provide a negative regulatory environment for EGFR transactivation linked to vascular remodeling induced by AngII. These novel findings may provide important information to target cardiovascular diseases under the enhanced renin angiotensin system.
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Takaguri
authors.forename: Heigoro
authors.initials: H
authors.lastname: Shirai
authors.forename: Keita
authors.initials: K
authors.lastname: Kimura
authors.forename: Akinari
authors.initials: A
authors.lastname: Hinoki
authors.forename: Kunie
authors.initials: K
authors.lastname: Eguchi
authors.forename: MaryEllen
authors.initials: M
authors.lastname: Carlile-Klusacek
authors.forename: Baohua
authors.initials: B
authors.lastname: Yang
authors.forename: Victor
authors.initials: V
authors.lastname: Rizzo
authors.forename: Satoru
authors.initials: S
authors.lastname: Eguchi
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005372:Filipin / Q000494:pharmacology; D018014:Gene Transfer Techniques; D006984:Hypertrophy / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D051242:Caveolin 1; D044140:Receptor, Angiotensin, Type 1; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D000804:Angiotensin II; D005372:Filipin; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat; D002118:Calcium