Metalloprotease inhibitor blocks angiotensin II-induced migration through inhibition of epidermal growth factor receptor transactivation.
In vascular smooth muscle cells (VSMCs), angiotensin II (AngII) induces transactivation of the EGF receptor (EGFR) which involves a metalloprotease that stimulates processing of heparin-binding EGF from its precursor. However, the identity and pharmacological sensitivity of the metalloprotease remain unclear. Here, we screened the effects of several metalloprotease inhibitors on AngII-induced EGFR transactivation in VSMCs. We found that an N-phenylsulfonyl-hydroxamic acid derivative [2R-[(4-biphenylsulfonyl)amino]-N-hydroxy-3-phenylpropinamide] (BiPS), previously known as matrix metalloprotease (MMP)-2/9 inhibitor, markedly inhibited AngII-induced EGFR transactivation, whereas the MMP-2 or -9 inhibition by other MMP inhibitors failed to block the transactivation. BiPS markedly inhibited AngII-induced ERK activation and protein synthesis without affecting AngII-induced intracellular Ca2+ elevation. VSMC migration induced by AngII was also inhibited not only by an EGFR inhibitor but also by BiPS. Thus, BiPS is a specific candidate to block AngII-induced EGFR transactivation and subsequent growth and migration of VSMCs, suggesting its potency to prevent vascular remodeling.
Saito
Shuichi
S
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Frank
Gerald D
GD
Motley
Evangeline D
ED
Dempsey
Peter J
PJ
Utsunomiya
Hirotoshi
H
Inagami
Tadashi
T
Eguchi
Satoru
S
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C400001:N-biphenylsulfonylphenylalanine hydroxamic acid; D011480:Protease Inhibitors; D000804:Angiotensin II; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases