Pharmacological Inhibition of ADAM17 by a Human-Cross Reactive Antibody and Selective Inhibitor JG26 Prevents Vascular Fibrosis Induced by Angiotensin II in vivo and in vitro

UM > Faculty of Health Sciences > DEPARTMENT OF BIOMEDICAL SCIENCES

Status	已發表Published
	Pharmacological Inhibition of ADAM17 by a Human-Cross Reactive Antibody and Selective Inhibitor JG26 Prevents Vascular Fibrosis Induced by Angiotensin II in vivo and in vitro
	Kawai, T.; Forrester, S. J.; Eguchi, K.; Rizzo, V.; Eguchi, S.; Kwok, H. F.; Murphy, G.; Rossello, A.
	2016-05-01
Source Publication	Arteriosclerosis, Thrombosis, and Vascular Biology
Pages	Suppl 1 ---
Publication Place	Dallas, TX
Publisher	American Heart Association
Abstract	In cultured vascular smooth muscle cells (VSMCs), we have shown that a metalloprotease, ADAM17, mediates EGF receptor (EGFR) transactivation induced by angiotensin II (AngII). We have also shown that in mice with AngII infusion, EGFR inhibitor erlotinib prevents vessel remodeling independently from hypertension. In the present study, we hypothesized that pharmacological inhibition of ADAM17 prevents AngII-induced vascular fibrosis in vivo and in vitro. A novel human-cross reactive ADAM17 inhibitory antibody, A9(B8), (10 mg/kg ip on day 1 and 7) was utilized in C57Bl/6 mice with AngII infusion (1000 ng/kg/min for 2 weeks). A novel ADAM17 inhibitor JG26 (1 μM) was utilized in cultured rat aortic VSMCs stimulated with 100 nM AngII. A9(B8) but not control IgG treatment attenuated perivascular fibrosis and vascular hypertrophy in mouse coronary arteries (assessed by Sirius Red staining) infused with AngII. A9(B8) also attenuated cardiac hypertrophy (assessed by echocardiogram and heart body weight ratio) but not hypertension in mice with AngII infusion. In VSMCs, 30 min pretreatment of JG26 inhibited AngII-induced extracellular collagen accumulation at 48 h (assessed by a Sirius Red quantification kit). JG26 also inhibited AngII-induced EGFR transactivation (2 and 10 min) and ERK activation (10 min) in VSMCs. We conclude that inhibition of ADAM17 is an effective approach to attenuate pathophysiological cardiovascular remodeling in an AngII-dependent model of hypertension. These data highlight ADAM17 as a novel therapeutic target to prevent end-organ damage associated with hypertension
Keyword	Angiotensin II Signal Transduction EGFR
URL	View the original
Language	英語English
The Source to Article	PB_Publication
PUB ID	28839
Document Type	Conference paper
Collection	DEPARTMENT OF BIOMEDICAL SCIENCES Faculty of Health Sciences
Recommended Citation GB/T 7714	Kawai, T., Forrester, S. J.,Eguchi, K.,et al. Pharmacological Inhibition of ADAM17 by a Human-Cross Reactive Antibody and Selective Inhibitor JG26 Prevents Vascular Fibrosis Induced by Angiotensin II in vivo and in vitro[C], Dallas, TX:American Heart Association, 2016, Suppl 1 ---.
APA	Kawai, T.., Forrester, S. J.., Eguchi, K.., Rizzo, V.., Eguchi, S.., Kwok, H. F.., Murphy, G.., & Rossello, A. (2016). Pharmacological Inhibition of ADAM17 by a Human-Cross Reactive Antibody and Selective Inhibitor JG26 Prevents Vascular Fibrosis Induced by Angiotensin II in vivo and in vitro. Arteriosclerosis, Thrombosis, and Vascular Biology, Suppl 1 ---.

Files in This Item:
There are no files associated with this item.

If you have any objections to this item, please fill out the form below and the administrator will contact you as soon as possible.
Content:
Email：	*
Affiliation No.
Verification Code:	Refresh

Any comments and suggestions are welcomed.
Title:	*
Content:
Email：	*
Verification Code:	Refresh