ADAM17 Mediates Epidermal Growth Factor Receptor Transactivation and Vascular Smooth Muscle Cell Hypertrophy Induced by Angiotensin II

Ohtsu, Haruhiko; Dempsey, Peter J.; Frank, Gerald D.; Brǎiloiu, Eugen; Higuchi, Sadaharu; Suzuki, Hiroyuki; Nakashima, Hisashi; Eguchi, Kunie; Eguchi, Satoru

doi:10.1161/01.atv.0000236203.90331.d0

Cited by 121 publications

(54 citation statements)

References 32 publications

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“…Activation of transmembrane ADAM17 leads to the cleavage of inactive membrane-bound precursors and the production of their complementary active form (Heparin-binding EGF-like growth factor (HB-EGF), neuregulin, EGF, etc). Although some reports show G q -independent EGFR transactivation (48, 49), ADAM17-mediated HB-EGF shedding by AngII requires G q activation (45, 50) and subsequent ADAM17 Tyr 702 phosphorylation (51–53). The ADAM17-dependent EGFR transactivation causes hypertrophy and migration of VSMCs through the Ras/ERK pathway and the PI3K/Akt/mechanistic target of rapamycin (mTOR)/p70S6K/eukaryotic translation initiation factor 4E (eIF4E) pathway (51–53).…”

Section: Growth Factor Receptor Transactivationmentioning

confidence: 99%

“…Although some reports show G q -independent EGFR transactivation (48, 49), ADAM17-mediated HB-EGF shedding by AngII requires G q activation (45, 50) and subsequent ADAM17 Tyr 702 phosphorylation (51–53). The ADAM17-dependent EGFR transactivation causes hypertrophy and migration of VSMCs through the Ras/ERK pathway and the PI3K/Akt/mechanistic target of rapamycin (mTOR)/p70S6K/eukaryotic translation initiation factor 4E (eIF4E) pathway (51–53). In addition, BMX (bone marrow kinase), CHKA (choline kinase alpha) and TRIO [triple functional domain (PTPRF interacting)] have been identified as upstream signaling molecules required for AngII-induced EGFR transactivation by siRNA library screening (54).…”

Section: Growth Factor Receptor Transactivationmentioning

confidence: 99%

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AT1 receptor signaling pathways in the cardiovascular system

Kawai

Forrester

O’Brien

et al. 2017

Pharmacological Research

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The importance of the renin angiotensin aldosterone system in cardiovascular physiology and pathophysiology has been well described whereas the detailed molecular mechanisms remain elusive. The angiotensin II type 1 receptor (AT1 receptor) is one of the key players in the renin angiotensin aldosterone system. The AT1 receptor promotes various intracellular signaling pathways resulting in hypertension, endothelial dysfunction, vascular remodeling and end organ damage. Accumulating evidence shows the complex picture of AT1 receptor-mediated signaling; AT1 receptor-mediated heterotrimeric G protein-dependent signaling, transactivation of growth factor receptors, NADPH oxidase and ROS signaling, G protein-independent signaling, including the β-arrestin signals and interaction with several AT1 receptor interacting proteins. In addition, there is functional cross-talk between the AT1 receptor signaling pathway and other signaling pathways. In this review, we will summarize an up to date overview of essential AT1 receptor signaling events and their functional significances in the cardiovascular system.

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Section: Growth Factor Receptor Transactivationmentioning

confidence: 99%

Section: Growth Factor Receptor Transactivationmentioning

confidence: 99%

AT1 receptor signaling pathways in the cardiovascular system

Kawai

Forrester

O’Brien

et al. 2017

Pharmacological Research

Self Cite

182

126

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“…We have demonstrated that a metalloproteinase, a disintegrin and metallopeptidase domain 17 (ADAM17), is required for AngII-induced epidermal growth factor receptor (EGFR) transactivation in VSMCs 6 and that the ADAM17/EGFR activation mediates vascular remodeling in mice infused with AngII 7, 8 . Moreover, ADAM17 expression is enhanced in human AAA 9, 10 and ADAM17 silenced mice do not develop CaCl 2 -induced AAAs 9 .…”

Section: Introductionmentioning

confidence: 99%

Vascular ADAM17 (a Disintegrin and Metalloproteinase Domain 17) Is Required for Angiotensin II/β-Aminopropionitrile–Induced Abdominal Aortic Aneurysm

et al. 2017

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Angiotensin II (AngII)-activated epidermal growth factor receptor (EGFR) has been implicated in abdominal aortic aneurysm (AAA) development. In vascular smooth muscle cells (VSMC), AngII activates EGFR via a metalloproteinase, a disintegrin and metallopeptidase domain 17 (ADAM17). We hypothesized that AngII-dependent AAA development would be prevented in mice lacking ADAM17 in VSMCs. To test this concept, control and VSMC ADAM17 deficient mice were co-treated with AngII and a lysyl oxidase inhibitor, β-aminopropionitrile, to induce AAA. We found that 52.4% of control mice did not survive due to aortic rupture. All other surviving control mice developed AAA and demonstrated enhanced expression of ADAM17 in the AAA lesions. In contrast, all AngII and β-aminopropionitrile-treated VSMC ADAM17 deficient mice survived and showed reduction in external/internal diameters (51%/28%, respectively). VSMC ADAM17 deficiency was associated with lack of EGFR activation, interleukin-6 induction, ER/oxidative stress and matrix deposition in the abdominal aorta of treated mice. However, both VSMC ADAM17 deficient and control mice treated with AngII and β-aminopropionitrile developed comparable levels of hypertension. Treatment of C57Bl/6 mice with an ADAM17 inhibitory antibody but not with control IgG also prevented AAA development. In conclusion, VSMC ADAM17 silencing or systemic ADAM17 inhibition appears to protect mice from AAA formation. The mechanism appears to involve suppression of EGFR activation.

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“…ADAM (a disintegrin and metalloprotainase) proteins belong to a family of membrane spanning metalloprotainases that cleave ectodomains of several substrates including epidermal growth factor receptor (EGFR) ligands 8 . We have shown that ADAM17-mediated EGFR transactivation via heparin-binding EGF-like growth factor (HB-EGF) shedding is required for extracellular signal-regulated kinase (ERK) activation but not for intracellular Ca 2+ elevation or Rho kinase activation 9-11 . Also, ADAM17 expression is enhanced in neointima after angioplasty, and dominant-negative ADAM17 gene-transfer prevents neointimal hyperplasia 12 .…”

Section: Introductionmentioning

confidence: 99%

Vascular ADAM17 as a Novel Therapeutic Target in Mediating Cardiovascular Hypertrophy and Perivascular Fibrosis Induced by Angiotensin II

et al. 2016

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Angiotensin II (AngII) has been strongly implicated in hypertension and its complications. Evidence suggests the mechanisms by which angiotensin II (AngII) elevates blood pressure and enhances cardiovascular remodeling and damage may be distinct. However, the signal transduction cascade by which AngII specifically initiates cardiovascular remodeling such as hypertrophy and fibrosis remains insufficiently understood. In vascular smooth muscle cells, a metalloproteinase ADAM17 mediates epidermal growth factor receptor (EGFR) transactivation, which may be responsible for cardiovascular remodeling but not hypertension induced by AngII. Thus, the objective of this study was to test the hypothesis that activation of vascular ADAM17 is indispensable for vascular remodeling but not for hypertension induced by AngII. Vascular ADAM17 deficient mice and control mice were infused with AngII for 2 weeks. Control mice infused with AngII showed cardiac hypertrophy, vascular medial hypertrophy and perivascular fibrosis. These phenotypes were prevented in vascular ADAM17 deficient mice independent of blood pressure alteration. AngII infusion enhanced ADAM17 expression, EGFR activation and ER stress in the vasculature, which were diminished in ADAM17 deficient mice. Treatment with a human cross-reactive ADAM17 inhibitory antibody also prevented cardiovascular remodeling and ER stress but not hypertension in C57Bl/6 mice infused with AngII. In vitro data further supported these findings. In conclusion, vascular ADAM17 mediates AngII-induced cardiovascular remodeling via EGFR activation independent of blood pressure regulation. ADAM17 seems to be a unique therapeutic target for the prevention of hypertensive complications.

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ADAM17 Mediates Epidermal Growth Factor Receptor Transactivation and Vascular Smooth Muscle Cell Hypertrophy Induced by Angiotensin II

Cited by 121 publications

References 32 publications

AT1 receptor signaling pathways in the cardiovascular system

AT1 receptor signaling pathways in the cardiovascular system

Vascular ADAM17 (a Disintegrin and Metalloproteinase Domain 17) Is Required for Angiotensin II/β-Aminopropionitrile–Induced Abdominal Aortic Aneurysm

Vascular ADAM17 as a Novel Therapeutic Target in Mediating Cardiovascular Hypertrophy and Perivascular Fibrosis Induced by Angiotensin II

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