scholarly journals ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury

2021 ◽  
Author(s):  
Takafumi Minato ◽  
Midori Hoshizaki ◽  
Tomokazu Yamaguchi ◽  
Jianbo An ◽  
Mayumi Niiyama ◽  
...  
Keyword(s):  
Lung Injury ◽  
Enzymatic Activity ◽  
Therapeutic Strategy ◽  
Cell Entry ◽  
Mrna Levels ◽  
Receptor Binding Domain ◽  
Ang Ii ◽  
Cytokine Mrna ◽  
Angiotensin Converting Enzyme 2

Abstract Angiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is the carboxypeptidase to degrade angiotensin II (Ang II) to angiotensin 1-7 and improves the pathologies of cardiovascular disease and acute lung injury. To address whether the carboxypeptidase enzymatic activity of ACE2 is protective against COVID-19, we investigated the effects of B38-CAP, an ACE2-like enzyme, on SARS-CoV-2-induced lung injury. Expression of ACE2 protein was significantly downregulated in the lungs of SARS-CoV-2-infected hamsters. Recombinant S1 domain or receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein also directly downregulated ACE2 expression and elevated Ang II levels and considerably worsened acid-induced lung injury in hamsters. Treatment with B38-CAP downregulated Spike RBD-induced high Ang II levels, severe inflammation and pulmonary edema through its ACE2-like enzymatic activity. Consistently, elevated cytokine mRNA levels and impaired lung functions were improved by B38-CAP treatment. Moreover, in SARS-CoV-2-infected humanized ACE2 transgenic mice, B38-CAP significantly improved the pathologies of lung injury, alleviated the cytokine storms and downregulated viral RNA levels. These results provide the first experimental in vivo evidence that increasing ACE2-like enzymatic activity is a potential and powerful therapeutic strategy for lung pathologies in COVID-19.

scholarly journals ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury

2020 ◽  
Author(s):  
Takafumi Minato ◽  
Midori Hoshizaki ◽  
Tomokazu Yamaguchi ◽  
Jianbo An ◽  
Mayumi Niiyama ◽  
...  
Keyword(s):  
Lung Injury ◽  
Enzymatic Activity ◽  
Therapeutic Strategy ◽  
Cell Entry ◽  
Mrna Levels ◽  
Receptor Binding Domain ◽  
Ang Ii ◽  
Cytokine Mrna ◽  
Angiotensin Converting Enzyme 2

Abstract Angiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is the carboxypeptidase to degrade angiotensin II (Ang II) to angiotensin 1-7 and improves the pathologies of cardiovascular disease and acute lung injury. To address whether the carboxypeptidase enzymatic activity of ACE2 is protective against COVID-19, we investigated the effects of B38-CAP, an ACE2-like enzyme, on SARS-CoV-2-induced lung injury. Expression of ACE2 protein was significantly downregulated in the lungs of SARS-CoV-2-infected hamsters. Recombinant S1 domain or receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein also directly downregulated ACE2 expression and elevated Ang II levels and considerably worsened acid-induced lung injury in hamsters. Treatment with B38-CAP downregulated Spike RBD-induced high Ang II levels, severe inflammation and pulmonary edema through its ACE2-like enzymatic activity. Consistently, elevated cytokine mRNA levels and impaired lung functions were improved by B38-CAP treatment. Moreover, in SARS-CoV-2-infected humanized ACE2 transgenic mice, B38-CAP significantly improved the pathologies of lung injury, alleviated the cytokine storms and downregulated viral RNA levels. These results provide the first experimental in vivo evidence that increasing ACE2-like enzymatic activity is a potential and powerful therapeutic strategy for lung pathologies in COVID-19.

scholarly journals ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tomokazu Yamaguchi ◽  
Midori Hoshizaki ◽  
Takafumi Minato ◽  
Satoru Nirasawa ◽  
Masamitsu N. Asaka ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Acute Lung Injury ◽  
Angiotensin Ii ◽  
Lung Injury ◽  
Therapeutic Strategy ◽  
Cell Entry ◽  
Lung Edema ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2

AbstractAngiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is a carboxypeptidase that degrades angiotensin II, thereby improving the pathologies of cardiovascular disease or acute lung injury. Here we show that B38-CAP, an ACE2-like enzyme, is protective against SARS-CoV-2-induced lung injury. Endogenous ACE2 expression is downregulated in the lungs of SARS-CoV-2-infected hamsters, leading to elevation of angiotensin II levels. Recombinant Spike also downregulates ACE2 expression and worsens the symptoms of acid-induced lung injury. B38-CAP does not neutralize cell entry of SARS-CoV-2. However, B38-CAP treatment improves the pathologies of Spike-augmented acid-induced lung injury. In SARS-CoV-2-infected hamsters or human ACE2 transgenic mice, B38-CAP significantly improves lung edema and pathologies of lung injury. These results provide the first in vivo evidence that increasing ACE2-like enzymatic activity is a potential therapeutic strategy to alleviate lung pathologies in COVID-19 patients.

Effect of exposure in vivo to tributyltin oxide (TBTO) and ozone on cytokine mRNA levels

1995 ◽  
Vol 31 ◽  
pp. 6
Author(s):  
R.J. Vandebriel ◽  
M.P. Scott ◽  
J.A.H. Wijnands ◽  
L. Van Bree ◽  
C. Meredith ◽  
...  
Keyword(s):  
Mrna Levels ◽  
Cytokine Mrna ◽  
Exposure In Vivo

In vivo induction of functional FcγRI (CD64) on neutrophils and modulation of blood cytokine mRNA levels in cancer patients treated with G-CSF (rMetHuG-CSF)

1998 ◽  
Vol 100 (3) ◽  
pp. 550-556 ◽  
Author(s):  
Jean M. Michon ◽  
Alain Gey ◽  
Sandrine Moutel ◽  
Eric Tartour ◽  
Valerie Meresse ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Mrna Levels ◽  
Cytokine Mrna ◽  
In Vivo Induction

scholarly journals The Orphan Nuclear Receptors NURR1 and NGFIB Regulate Adrenal Aldosterone Production

2004 ◽  
Vol 18 (2) ◽  
pp. 279-290 ◽  
Author(s):  
Mary H. Bassett ◽  
Takashi Suzuki ◽  
Hironobu Sasano ◽  
Perrin C. White ◽  
William E. Rainey
Keyword(s):  
Kinase Inhibitor ◽  
Zona Glomerulosa ◽  
Zona Fasciculata ◽  
Related Factor ◽  
Mrna Levels ◽  
Ang Ii ◽  
Orphan Nuclear Receptors ◽  
Protein Levels ◽  
Aldosterone Production

Abstract Aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex is regulated by transcription of CYP11B2 (encoding aldosterone synthase). The effects of nerve growth factor-induced clone B (NGFIB) (NR4A1), Nur-related factor 1 (NURR1) (NR4A2), and steroidogenic factor-1 (SF-1) (NR5A1) on transcription of human CYP11B2 (hCYP11B2) and hCYP11B1 (11β-hydroxylase) were compared in human H295R adrenocortical cells. hCYP11B2 expression was increased by NGFIB and NURR1. Although hCYP11B1 was activated by SF-1, cotransfection with SF-1 inhibited activation of hCYP11B2 by NGFIB and NURR1. NGFIB and NURR1 transcript and protein levels were strongly induced by angiotensin (Ang) II, the major regulator of hCYP11B2 expression in vivo. Sequential deletion and mutagenesis of the hCYP11B2 promoter identified two functional NGFIB response elements (NBREs), one located at −766/−759 (NBRE-1) and the previously studied Ad5 element at −129/−114. EMSAs suggested that both elements bound NGFIB and NURR1. In human adrenals, NURR1 immunoreactivity was preferentially localized in the zona glomerulosa and to a lesser degree in the zona fasciculata, whereas NGFIB was detected in both zones. The calmodulin kinase inhibitor KN93 partially blocked K+-stimulated transcription of NGFIB and NURR1. KN93 partially inhibited the effect of Ang II on NURR1 mRNA levels but did not modify the effect on expression of NGFIB. Mutation of the NBRE-1, Ad5, and Ad1/cAMP response element (CRE) cis-elements reduced both basal and Ang II-induced levels of hCYP11B2, demonstrating that all three elements are important for maximal transcriptional activity. Our results suggest that NGFIB and NURR1 are key regulators of hCYP11B2 expression and may partially mediate the regulation of hCYP11B2 by Ang II.

scholarly journals Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

2021 ◽  
Author(s):  
Vincent Dussupt ◽  
Rajeshwer S. Sankhala ◽  
Letzibeth Mendez-Rivera ◽  
Samantha M. Townsley ◽  
Fabian Schmidt ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Low Dose ◽  
Viral Escape ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Viral Inactivation ◽  
Angiotensin Converting Enzyme 2 ◽  
Therapeutic Monoclonal Antibodies ◽  
Potent Protection

AbstractPrevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

scholarly journals The renin-angiotensin system: going beyond the classical paradigms

2019 ◽  
Vol 316 (5) ◽  
pp. H958-H970 ◽  
Author(s):  
Robson Augusto Souza Santos ◽  
Gavin Y. Oudit ◽  
Thiago Verano-Braga ◽  
Giovanni Canta ◽  
Ulrike Muscha Steckelings ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Protective Effects ◽  
Ang Ii ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Amino Terminal ◽  
Angiotensin Peptides ◽  
Protective Actions

Thirty years ago, a novel axis of the renin-angiotensin system (RAS) was unveiled by the discovery of angiotensin-(1−7) [ANG-(1−7)] generation in vivo. Later, angiotensin-converting enzyme 2 (ACE2) was shown to be the main mediator of this reaction, and Mas was found to be the receptor for the heptapeptide. The functional analysis of this novel axis of the RAS that followed its discovery revealed numerous protective actions in particular for cardiovascular diseases. In parallel, similar protective actions were also described for one of the two receptors of ANG II, the ANG II type 2 receptor (AT2R), in contrast to the other, the ANG II type 1 receptor (AT1R), which mediates deleterious actions of this peptide, e.g., in the setting of cardiovascular disease. Very recently, another branch of the RAS was discovered, based on angiotensin peptides in which the amino-terminal aspartate was replaced by alanine, the alatensins. Ala-ANG-(1−7) or alamandine was shown to interact with Mas-related G protein-coupled receptor D, and the first functional data indicated that this peptide also exerts protective effects in the cardiovascular system. This review summarizes the presentations given at the International Union of Physiological Sciences Congress in Rio de Janeiro, Brazil, in 2017, during the symposium entitled “The Renin-Angiotensin System: Going Beyond the Classical Paradigms,” in which the signaling and physiological actions of ANG-(1−7), ACE2, AT2R, and alatensins were reported (with a focus on noncentral nervous system-related tissues) and the therapeutic opportunities based on these findings were discussed.

scholarly journals Thioredoxin Reductase-1 Inhibition Augments Endogenous Glutathione-Dependent Antioxidant Responses in Experimental Bronchopulmonary Dysplasia

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Stephanie B. Wall ◽  
Rachael Wood ◽  
Katelyn Dunigan ◽  
Qian Li ◽  
Rui Li ◽  
...  
Keyword(s):  
Lung Injury ◽  
Thioredoxin Reductase ◽  
Antioxidant Defenses ◽  
Mrna Levels ◽  
Newborn Mice ◽  
Antioxidant Responses ◽  
Thioredoxin Reductase 1 ◽  
Gpx Activity

Background. Aurothioglucose- (ATG-) mediated inhibition of thioredoxin reductase-1 (TXNRD1) improves alveolarization in experimental murine bronchopulmonary dysplasia (BPD). Glutathione (GSH) mediates susceptibility to neonatal and adult oxidative lung injury. We have previously shown that ATG attenuates hyperoxic lung injury and enhances glutathione- (GSH-) dependent antioxidant defenses in adult mice. Hypothesis. The present studies evaluated the effects of TXNRD1 inhibition on GSH-dependent antioxidant defenses in newborn mice in vivo and lung epithelia in vitro. Methods. Newborn mice received intraperitoneal ATG or saline prior to room air or 85% hyperoxia exposure. Glutamate-cysteine ligase (GCL) catalytic (Gclc) and modifier (Gclm) mRNA levels, total GSH levels, total GSH peroxidase (GPx) activity, and Gpx2 expression were determined in lung homogenates. In vitro, murine transformed club cells (mtCCs) were treated with the TXNRD1 inhibitor auranofin (AFN) or vehicle in the presence or absence of the GCL inhibitor buthionine sulfoximine (BSO). Results. In vivo, ATG enhanced hyperoxia-induced increases in Gclc mRNA levels, total GSH contents, and GPx activity. In vitro, AFN increased Gclm mRNA levels, intracellular and extracellular GSH levels, and GPx activity. BSO prevented AFN-induced increases in GSH levels. Conclusions. Our data are consistent with a model in which TXNRD1 inhibition augments hyperoxia-induced GSH-dependent antioxidant responses in neonatal mice. Discrepancies between in vivo and in vitro results highlight the need for methodologies that permit accurate assessments of the GSH system at the single-cell level.

Co-Expression and Localization of Angiotensin-Converting Enzyme-2 (ACE2) and the Transmembrane Serine Protease 2 (TMPRSS2) in Paranasal Ciliated Epithelium of Patients with Chronic Rhinosinusitis

2022 ◽  
pp. 194589242110596
Author(s):  
Tomohiro Kawasumi ◽  
Sachio Takeno ◽  
Takashi Ishino ◽  
Tsutomu Ueda ◽  
Takao Hamamoto ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Chronic Rhinosinusitis ◽  
Cell Entry ◽  
Ciliated Epithelium ◽  
Mrna Levels ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Tnf Α ◽  
Ifn Γ ◽  
Transmembrane Serine Protease

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme-2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) as a primary receptor for invasion. Cell entry by the virus requires the co-expression of these molecules in the host cells. Objective We investigated ACE2 and TMPRSS2 expression and localization in paranasal epithelium of eosinophilic chronic rhinosinusitis (ECRS) patients (n = 38), non-ECRS (n = 31), and healthy controls (n = 25). CRS inflammatory patterns are characterized by the type of cytokines; we investigated whether inflammatory endotypes are associated with cell-entry molecules, as this could be linked to susceptibility to SARS-CoV-2 infection. Methods The ACE2, TMPRSS2, and other inflammatory cytokine mRNA levels were assessed by quantitative RT-PCR. The localizations of ACE2- and TMPRSS2-positive cells were examined with immunofluorescent double-staining using laser scanning confocal microscopy (LSCM). Results The non-ECRS patients showed significantly increased ACE2 and TMPRSS2 mRNA expressions compared to the ECRS patients. The CRS patients’ ACE2 and TMPRSS2 mRNA levels were positively correlated with IFN-γ ( r = 0.3227 and r = 0.3264, respectively) and TNF-α ( r = 0.4008, r = 0.3962, respectively). ACE2 and TMPRSS2 were negatively correlated with tissue eosinophils ( r =  −0.3308, r =  −0.3112, respectively), but not with IL-13. ACE2 mRNA levels were positively correlated with TMPRSS2 ( r = 0.7478). ACE2 and TMPRSS2 immunoreactivities were localized mainly in the epithelial ciliated cells, as confirmed by co-staining with TMPRSS2 and acetylated α-tubulin, a cilia organelle marker. Using LSCM imaging, we observed higher expressions of these molecules in the non-ECRS patients versus the ECRS patients. Conclusion ECRS patients with type 2 inflammation showed decreased ACE2 and TMPRSS2 expressions in their sinus mucosa. ACE2 and TMPRSS2 regulation seems to be positively related to IFN-γ and TNF-α production in CRS patients; ACE2 and TMPRSS2 were co-expressed in the ciliated epithelium of their paranasal mucosa, implicating the paranasal epithelium as a portal for initial infection and transmission.

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