Metalloprotease inhibitor blocks angiotensin II-induced migration through inhibition of epidermal growth factor receptor transactivation.
Metalloprotease inhibitor blocks angiotensin II-induced migration through inhibition of epidermal growth factor receptor transactivation.
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DOI：
10.1016/s0006-291x(02)00595-8
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发表时间：
2002-06
影响因子：
3.1
通讯作者：
Shuichi Saito;G. D. Frank;E. Motley;P. Dempsey;H. Utsunomiya;T. Inagami;S. Eguchi
中科院分区：
文献类型：
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作者：
Shuichi Saito;G. D. Frank;E. Motley;P. Dempsey;H. Utsunomiya;T. Inagami;S. Eguchi
在血管平滑肌细胞(VSMCs)中，血管紧张素II(AngII)诱导EGF受体(EGFR)的反式激活，该受体涉及一种金属蛋白水解酶，刺激其前体对肝素结合的EGF进行加工。然而，金属蛋白水解酶的特性和药理敏感性仍不清楚。在这里，我们筛选了几种金属蛋白酶抑制剂对血管紧张素转换酶诱导的血管平滑肌细胞EGFR反式激活的影响。我们发现，N-苯磺酰异羟肟酸衍生物{2R-[(4-biphenylsulfonyl)amino]-N-hydroxy-3-phenylpropinamide}(BIPS)，以前被称为基质金属蛋白酶-2/9抑制剂，可显著抑制血管紧张素Ⅱ诱导的EGFR反式激活，而其他基质金属蛋白酶抑制剂对基质金属蛋白酶-2或-9的抑制作用不能阻断这种反式激活。BIPS明显抑制AngII诱导的ERK激活和蛋白质合成，但不影响AngII诱导的细胞内钙升高。血管紧张素Ⅱ诱导的VSMC迁移不仅可被EGFR抑制剂抑制，还可被BIPS抑制。因此，BIPS是阻断血管紧张素Ⅱ诱导的EGFR反式激活和随后的VSMCs生长和迁移的特定候选者，这表明其具有防止血管重构的效力。
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.