EGF Receptor Transactivation in Angiotensin II and Endothelin Control of Vascular Protein Synthesis in vivo

2004 ◽  
Vol 44 (Supplement 1) ◽  
pp. S20-S23 ◽  
Author(s):  
Pierre Beaucage ◽  
Pierre Moreau
Keyword(s):  
Protein Synthesis ◽  
Angiotensin Ii ◽  
Egf Receptor ◽  
Receptor Transactivation

Abstract 557: 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

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Tatsuo Kawai ◽  
Steven J Forrester ◽  
Kunie Eguchi ◽  
Victor Rizzo ◽  
Satoru Eguchi ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Egf Receptor ◽  
Weight Ratio ◽  
Organ Damage ◽  
Inhibitory Antibody ◽  
Egfr Transactivation ◽  
Pharmacological Inhibition ◽  
Sirius Red

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.

Position of Src tyrosine kinases in the interaction between angiotensin II and endothelin in in vivo vascular protein synthesis

2005 ◽  
Vol 23 (2) ◽  
pp. 329-335 ◽  
Author(s):  
Pierre Beaucage ◽  
Marc Iglarz ◽  
Marc Servant ◽  
Rhian M Touyz ◽  
Pierre Moreau
Keyword(s):  
Protein Synthesis ◽  
Angiotensin Ii ◽  
Tyrosine Kinases ◽  
Src Tyrosine Kinases

scholarly journals Platelet-Derived Growth Factor Receptor Transactivation Mediates the Trophic Effects of Angiotensin II In Vivo

Hypertension ◽  
2004 ◽  
Vol 44 (2) ◽  
pp. 195-202 ◽  
Author(s):  
Darren J. Kelly ◽  
Alison J. Cox ◽  
Renae M. Gow ◽  
Yuan Zhang ◽  
Bruce E. Kemp ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Trophic Effects ◽  
Receptor Transactivation

scholarly journals Specific endothelial heparin-binding EGF-like growth factor deletion ameliorates renal injury induced by chronic angiotensin II infusion

2016 ◽  
Vol 311 (4) ◽  
pp. F695-F707 ◽  
Author(s):  
Fenghua Zeng ◽  
Lance A. Kloepfer ◽  
Charlene Finney ◽  
André Diedrich ◽  
Raymond C. Harris
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Egf Receptor ◽  
Kidney Diseases ◽  
Ang Ii ◽  
Heparin Binding ◽  
Egfr Activation ◽  
Perivascular Area ◽  
Endothelial Integrity

Transactivation of EGF receptor (EGFR) by angiotensin II (Ang II) plays important roles in the initiation and progression of chronic kidney diseases. Studies suggest that heparin-binding EGF-like factor (HB-EGF) may be a critical mediator in this process, but its role in vivo has not been investigated. In the current study, we found that in response to Ang II infusion, kidneys from endothelial HB-EGF deletion mice had significantly reduced EGFR activation compared with controls. Meanwhile, deletion of endothelial HB-EGF expression decreased Ang II infusion related renal injury, as demonstrated by 1) less albuminuria; 2) less glomerulosclerosis; 3) preserved endothelial integrity and decreased podocyte injury, as shown by greater glomerular tuft area and WT1-positive cells, and fewer apoptotic cells measured by cleaved caspase 3 staining; 4) reduced inflammation in the perivascular area and interstitium measured by F4/80 and CD3 immunostaining; and 5) reduced renal fibrosis. In conclusion, our results suggest that shedding of HB-EGF from endothelium plays an important role in Ang II-induced renal injury by linking Ang II-AT1R with EGFR transactivation. Inhibition of HB-EGF shedding could be a potential therapeutic strategy for chronic kidney disease.

Angiotensin II increases the release of endothelin-I from human cultured endothelial cells but does not regulate its circulating levels

1999 ◽  
Vol 96 (3) ◽  
pp. 261-270 ◽  
Author(s):  
Claudio FERRI ◽  
Giovambattista DESIDERI ◽  
Roberta BALDONCINI ◽  
Cesare BELLINI ◽  
Marco VALENTI ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Protein Synthesis ◽  
Angiotensin Ii ◽  
At1 Receptor ◽  
Dependent Manner ◽  
Synthesis Inhibitor ◽  
Endothelin 1 ◽  
Cultured Endothelial Cells

We investigated the effect of angiotensin II on endothelin-1 secretion in vitro and in vivo. In vivo, angiotensin II was given intravenously to 23 essential hypertensive and 8 control subjects according to different protocols: Study A, 1.0 ngċmin-1ċkg-1 and 3.0 ngċmin-1ċkg-1 angiotensin II for 30 min each; Study B, 1.0 ngċmin-1ċkg-1 and 3.0 ngċmin-1ċkg-1 angiotensin II for 120 min each; Study C, 3.0 ngċmin-1ċkg-1 angiotensin II for 30 min followed by a dose increment of 3.0 ngċmin-1ċkg-1 every 30 min until mean blood pressure levels increased by 25 mmHg; Study D, 1.0 ngċmin-1ċkg-1 followed by 3.0 ngċmin-1ċkg-1 angiotensin II for 60 min each on two different NaCl diets (either 20 mmol NaCl/day or 220 mmol NaCl/day, both for 1 week). In all in vivo studies neither plasma nor urine endothelin-1 levels changed with angiotensin II infusion. In contrast, angiotensin II (10-9, 10-8, 10-7 mol/l) stimulated endothelin-1 secretion from cultured human vascular endothelial cells derived from umbilical cord veins in a time- and dose-dependent manner. The in vitro angiotensin II effects were abolished by candesartan cilexetil, an inhibitor of the membrane-bound AT1 receptor, and also by actinomycin D, an RNA synthesis inhibitor, and cycloheximide, a protein synthesis inhibitor, indicating that endothelin-1 release depended on AT1 receptor subtype and de novo protein synthesis. Our findings indicate that angiotensin II regulates endothelin-1 release by cultured endothelial cells through an AT1 receptor-dependent pathway, but does not influence circulating endothelin-1 levels in vivo.

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