Biochemical and Biophysical Research Communications
Metalloprotease inhibitor blocks angiotensin II-induced migration through inhibition of epidermal growth factor receptor transactivation
Section snippets
Materials and methods
Reagents and antibodies. AngII and H2O2 was obtained from Sigma. All MMP inhibitors, tissue inhibitor of metalloproteases (TIMP)-1, A23187, and AG1478 were purchased from Calbiochem. Phospho-specific anti-EGFR antibody and phospho-specific anti-JAK2 antibody were purchased from Bio-Source International. Anti-EGFR antibody and phospho-specific anti-ERK antibody were purchased from Santa Cruz Biotechnology.
Cell culture. VSMCs were prepared from thoracic aorta of 12-week-old male Sprague–Dawley
Screening of various MMP inhibitors on AngII-induced EGFR transactivation
To determine whether AngII-induced EGFR transactivation involves MMP activation, the effects of various MMP inhibitors on EGFR phosphorylation at Tyr1068, a Grb2-binding site, were examined (Fig. 1A). An N-phenylsulfonyl-hydroxamic acid derivative, BiPS, previously known as MMP-2/9 inhibitor-II [25] and CGS27023, also known as MMP-3 inhibitor-II [28], markedly inhibited AngII-induced EGFR transactivation. However, thiadiazol urea matrix metalloprotease inhibitors, also known as MMP-3
Discussion
The major findings of the present study are (i) a N-phenylsulfonyl-hydroxamic acid-derived metalloprotease inhibitor, BiPS, selectively inhibited AngII-induced EGFR transactivation without affecting intracellular Ca2+ elevation or JAK2 activation in VSMCs, (ii) Ca2+ ionophore- and H2O2-induced EGFR transactivation and AngII-induced ERK activation were inhibited by BiPS, and (iii) AngII-induced VSMC growth and migration were also blocked by BiPS through inhibition of EGFR transactivation. These
Acknowledgements
We thank Trinita Fitzgerald and Kunie Eguchi for their excellent technical assistance. This work was supported in part by the research Grants HL58205 (T. Inagami), HL03320 (E.D. Motley), and DK20593 (T. Inagami) from the National Institute of Health, Merck Postdoctoral Science Fellowship (G.D. Frank), an American Heart Association Scientist Development Grant (S. Eguchi), and Vanderbilt University Diabetes Center Pilot and Feasibility Proposal (S. Eguchi).
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