ADAM17-Mediated Shedding of Inflammatory Cytokines in Hypertension

Queiroz, Thyago M.; Lakkappa, Navya; Lazartigues, Eric

doi:10.3389/fphar.2020.01154

Cited by 50 publications

(59 citation statements)

References 127 publications

(169 reference statements)

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“…First, we observed a spike-induced down-regulation of the anti-inflammatory RAS axis and up-regulation of the proinflammatory AT1/NOX2 axis, which may lead to an increase in cytokine release [ 32 , 63 , 64 ] mediated by NOX2-derived ROS [ 54 , 65 ]. Second, ADAM17 is not only involved in shedding of ACE2 [ 49–51 ], but in the release several cytokines [ 66 ]. It is well-known that ADAM17 or TACE (TNF-α -converting enzyme) releases TNF-α from cells [ 67 ], and that ADAM17 promotes IL-6/soluble IL-6 receptor release [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19

et al. 2021

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The key link between renin–angiotensin system (RAS) and COVID-19 is ACE2 (angiotensin-converting enzyme 2), which acts as a double-edged sword, because ACE2 increases the tissue anti-inflammatory response but it is also the entry receptor for the virus. There is an important controversy on several drugs that regulate RAS activity and possibly ACE2, and are widely used, particularly by patients most vulnerable to severe COVID-19. In the lung of healthy rats, we observed that candesartan (an angiotensin type-1, AT1, receptor blocker; ARB) and captopril (an ACE inhibitor; ACEI) up-regulated expression of tissue ACE2 and RAS anti-inflammatory axis receptors (AT2 and Mas receptors). This effect was particularly pronounced in rats with metabolic syndrome (obesity, increased blood pressure and hyperglycemia) and aged rats. Treatment of cultures of human type-II pneumocytes with candesartan or captopril induced up-regulation of ACE2 expression in cells. Treatment with viral spike protein induced a decrease in full-length (i.e. transmembrane) ACE2, an increase in levels of a short intracellular ACE2 polypeptide and an increase in ADAM17 activity in cells, together with an increase in levels of soluble ACE2 and major proinflammatory cytokines in the culture medium. Spike protein-induced changes and levels of spike protein internalization in cells were inhibited by pretreatment with the above-mentioned drugs. The results suggest that these drugs increase ACE2 levels and promote the anti-inflammatory RAS axis in the lung. Furthermore, possible up-regulation of viral entry by the drug-induced increase in expression of transmembrane ACE2 is counteracted by additional mechanisms, particularly by drug-induced inhibition of ADAM17 activity.

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Section: Discussionmentioning

confidence: 99%

Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19

et al. 2021

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“…ADAM17 is a metalloproteinase that has been identified as the sheddase for a broad range of membrane-bound proteins expressed on numerous cell types including haematopoietic cells [ 15–17 ]. It plays a major role in chemokine/cytokine shedding, cell signalling, proliferation and growth [ 18 ]. As you will discover in this review, ADAM17 has both beneficial and detrimental effects.…”

Section: What Is Adam17?mentioning

confidence: 99%

Implications of ADAM17 activation for hyperglycaemia, obesity and type 2 diabetes

et al. 2021

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In this review, we focus specifically on the role that the metalloproteinase, A Disintegrin and Metalloproteinase 17 [ADAM17] plays in the development and progression of the metabolic syndrome. There is a well-recognised link between the ADAM17 substrate tumour necrosis factor α (TNF-α) and obesity, inflammation and diabetes. In addition, knocking out ADAM17 in mice leads to an extremely lean phenotype. Importantly, ADAM17-deficient mice exhibit one of the most pronounced examples of hypermetabolism in rodents to date. It is vital to further understand the mechanistic role that ADAM17 plays in the metabolic syndrome. Such studies will demonstrate that ADAM17 is a valuable therapeutic target to treat obesity and diabetes.

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“…shedding of the enzymatically active ectodomain of ACE2 by the metalloproteinase ADAM-17 (485), which also contributes to the shedding of inflammatory cytokines (333). ADAM17 and TMPRSS2 compete for ACE2 processing, but only cleavage by the latter promotes virus-driven cell entry (158).…”

Section: Viral Acquisition Ace2 and The Renin-angiotensin Redox Signalling Axismentioning

confidence: 99%

COVID-19: A Redox Disease—What a Stress Pandemic Can Teach Us About Resilience and What We May Learn from the Reactive Species Interactome About Its Treatment

Cumpstey

Clark

Santolini

et al. 2021

Antioxidants & Redox Signaling

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Significance: SARS-CoV-2, the virus causing COVID-19, affects every aspect of human life by challenging bodily, socio-economic and political systems at unprecedented levels. As vaccines become available, their distribution, safety and efficacy against emerging variants remain uncertain, and specific treatments are lacking.Recent Advances: Initially affecting the lungs, COVID-19 is a complex multi-systems disease that disturbs whole-body redox balance and can be long-lasting (Long-COVID). Numerous risk factors have been identified, but reasons for variations in susceptibility to infection, disease severity and outcome are poorly understood. The reactive species interactome (RSI) was recently introduced as a framework to conceptualise how cells and whole organisms sense, integrate and accommodate stress. Critical Issues:We here consider COVID-19 as a redox disease, offering a holistic perspective of its effects on the human body, considering the vulnerability of complex interconnected systems with multi-organ/multi-level interdependencies. Host/viral glycan interactions underpin SARS-CoV-2's extraordinary efficiency in gaining cellular access, crossing the epithelial/endothelial barrier to spread along the vascular/lymphatic endothelium, and evading antiviral/antioxidant defences. An inflammation-

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ADAM17-Mediated Shedding of Inflammatory Cytokines in Hypertension

Cited by 50 publications

References 127 publications

Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19

Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19

Implications of ADAM17 activation for hyperglycaemia, obesity and type 2 diabetes

COVID-19: A Redox Disease—What a Stress Pandemic Can Teach Us About Resilience and What We May Learn from the Reactive Species Interactome About Its Treatment

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