A Disintegrin and Metalloprotease 17 in the Cardiovascular and Central Nervous Systems

Xu, Jiaxi; Mukerjee, Snigdha; Silva-Alves, Cristiane R. A.; Carvalho‐Galvão, Alynne; Cruz, José Jaime da; Balarini, Camille M.; Braga, Valdir A.; Lazartigues, Eric; França-Silva, Maria S.

doi:10.3389/fphys.2016.00469

Cited by 52 publications

(49 citation statements)

References 172 publications

(208 reference statements)

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“…Although ADAM17 (aka TNFα convertase) was originally discovered as a key sheddase in the formation of cytokines, such as TNFα, its wide spectrum of substrates 19 also highlights its important role, beyond inflammation, in the CNS and cardiovascular system. 7 An opposite relationship between ADAM17 and ACE2, a pivotal member of the compensatory RAS, was discovered by the observation of increased sACE2 levels in the culture medium of cells transfected with ADAM17. 20 ACE2 is a cell-surface-bound enzyme, with its catalytic site exposed to the extracellular surface, 21 therefore, ADAM17-mediated ectodomain shedding might compromise the RAS compensatory axis by impairing ACE2 enzymatic activity, or its ability to process Ang II on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Sriramula

Xia

et al. 2017

Circulation Research

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Rationale Neurogenic hypertension is characterized by an increase in sympathetic activity and often resistance to drug treatments. We previously reported that it is also associated with a reduction of Angiotensin Converting Enzyme 2 (ACE2) and an increase in A Disintegrin And Metalloprotease 17 (ADAM17) activity in experimental hypertension. In addition, while multiple cells within the central nervous system have been involved in the development of neurogenic hypertension, the contribution of ADAM17 has not been investigated. Objective To assess the clinical relevance of this ADAM17-mediated ACE2 shedding in hypertensive patients and further identify the cell types and signaling pathways involved in this process. Methods and Results Using a mass spectrometry-based assay, we identified ACE2 as the main enzyme converting Ang II into Ang-(1–7) in human cerebrospinal fluid (CSF). We also observed an increase in ACE2 activity in the CSF of hypertensive patients, which was correlated with systolic blood pressure. Moreover, the increased level of tumor necrosis factor (TNF)-α in those CSF samples confirmed that ADAM17 was up-regulated in the hypertensive patients’ brain. To further assess the interaction between brain renin-angiotensin system and ADAM17, we generated mice lacking Angiotensin II type 1 receptors (AT1R) specifically on neurons. Our data reveal that despite expression on astrocytes and other cells types in the brain, ADAM17 up-regulation during DOCA-salt hypertension occurs selectively on neurons and neuronal AT1R are indispensable to this process. Mechanistically, reactive oxygen species (ROS) and extracellular signal-regulated kinase (ERK) were found to mediate ADAM17 activation. Conclusions Our data demonstrate that AT1R promote ADAM17-mediated ACE2 shedding in the brain of hypertensive patients, leading to a loss in compensatory activity during neurogenic hypertension.

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Section: Discussionmentioning

confidence: 99%

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Sriramula

Xia

et al. 2017

Circulation Research

Self Cite

159

166

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“…Note that while the protein expression analysis of TNFα did not show any enhancement in AAA, the experiment did not measure the potential conversion of pro-TNFα to mature and active TNFα by ADAM17. Moreover, ADAM17 has additional diverse substrates and many regulatory mechanisms 26 . Therefore, further research is required to identify potentially new pathways through which ADAM17 regulates AAA.…”

Section: Discussionmentioning

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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“…ADAM17 is a component of the plasma membrane [ 79 , 80 ], and also called tumor necrosis factor-α converting enzyme (TACE). TACE, in addition to being capable of cleaving mIL-6R to produce sIL-6R, can also cleave ligands for ErbB, including transforming growth factor-α and amphiregulin.…”

Section: Metzincin Proteases Contribute To the Formation Sil-6rmentioning

confidence: 99%

A Role for Soluble IL-6 Receptor in Osteoarthritis

Akeson

Malemud

2017

JFMK

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Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines present at elevated levels in the synovial fluid of individuals with confirmed clinical diagnosis of rheumatoid arthritis (RA) and osteoarthritis (OA). The mechanism of action of IL-6 was shown to involve its capacity to interact with a membrane-bound IL-6 receptor (mIL-6Rα), also known as the “classical” IL-6 pathway, or through its interaction with a soluble IL-6 receptor (sIL-6R) termed the “trans-signaling” pathway. Activation of downstream signaling is transduced via these IL-6 receptors and principally involves the Janus Kinase/Signal Transduction and Activators of Transcription (JAK/STAT) signaling pathway that is further regulated by glycoprotein-130 (gp130) interacting with the IL-6/mIL-6R complex. Phosphorylation of STAT proteins via JAK activation facilitates STAT proteins to act as transcription factors in inflammation. However, the biological function(s) of the sIL-6R in human chondrocytes requires further elucidation, although we previously showed that exogenous sIL-6R significantly suppressed the synthesis of neutrophil gelatinase-associated lipocalin (NGAL) in the immortalized line of human chondrocytes, C28/I2. NGAL was shown to regulate the activity of matrix metalloproteinase-9 (MMP-9), whose activity is crucial in OA for the destruction of articular cartilage. The “shedding” of sIL-6R from the plasma membrane is carried out by a family of enzymes known as A Distintegrin and Metalloproteinase (ADAM), which are also elevated in OA. In this paper, we have systematically reviewed the role played by IL-6 in OA. We have proposed that sIL-6R may be an important target for future drug development in OA by ameliorating cartilage extracellular protein degradation.

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A Disintegrin and Metalloprotease 17 in the Cardiovascular and Central Nervous Systems

Cited by 52 publications

References 172 publications

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

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

A Role for Soluble IL-6 Receptor in Osteoarthritis

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A Disintegrin and Metalloprotease 17 in the Cardiovascular and Central Nervous Systems

Cited by 52 publications

References 172 publications

Clinical Relevance and Role of Neuronal AT 1 Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Clinical Relevance and Role of Neuronal AT 1 Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

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

A Role for Soluble IL-6 Receptor in Osteoarthritis

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Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension