scholarly journals Imatinib (STI571) Inhibits the Expression of Angiotensin-Converting Enzyme 2 and Cell Entry of the SARS-CoV-2-Derived Pseudotyped Viral Particles

2021 ◽  
Vol 22 (13) ◽  
pp. 6938
Author(s):  
You-Zhe Lin ◽  
Yi-Chun Shen ◽  
Wan-Rong Wu ◽  
Wei-Jan Wang ◽  
Yuan-Liang Wang ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Cell Entry ◽  
Cell Surface Receptor ◽  
Renal Tubules ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2

A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19.

Role for tyrosine kinases in carbachol-regulated Ca entry into colonic epithelial cells

1995 ◽  
Vol 268 (1) ◽  
pp. C154-C161 ◽  
Author(s):  
G. Bischof ◽  
B. Illek ◽  
W. W. Reenstra ◽  
T. E. Machen
Keyword(s):  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Divalent Cations ◽  
Tyrosine Phosphatase ◽  
Inhibitory Effect ◽  
Colonic Epithelial Cells

We studied a possible role of tyrosine kinases in the regulation of Ca entry into colonic epithelial cells HT-29/B6 using digital image processing of fura 2 fluorescence. Both carbachol and thapsigargin increased Ca entry to a similar extent and Ca influx was reduced by the tyrosine kinase inhibitor genistein (50 microM). Further experiments were performed in solutions containing 95 mM K to depolarize the membrane potential, and the effects of different inhibitors on influx of Ca, Mn, and Ba were compared. Genistein, but not the inactive analogue daidzein nor the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2- methylpiperazine, decreased entry of all three divalent cations by 47-59%. In high-K solutions, carbachol or thapsigargin both caused intracellular Ca to increase to a plateau of 223 +/- 19 nM. This plateau was reduced by the tyrosine kinase inhibitors genistein (to 95 +/- 8 nM), lavendustin A (to 155 +/- 17 nM), and methyl-2,5-dihydroxycinnamate (to 39 +/- 3 nM). Orthovanadate, a protein tyrosine phosphatase inhibitor, prevented the inhibitory effect of genistein. Ca pumping was unaffected by genistein. Carbachol increased tyrosine phosphorylation (immunoblots with anti-phosphotyrosine antibodies) of 110-, 75-, and 70-kDa proteins, and this phosphorylation was inhibited by genistein. We conclude that carbachol and thapsigargin increase Ca entry, and tyrosine phosphorylation of some key proteins may be important for regulating this pathway.

TEL/PDGFβR Induces Hematologic Malignancies in Mice That Respond to a Specific Tyrosine Kinase Inhibitor

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1707-1714 ◽  
Author(s):  
Michael H. Tomasson ◽  
Ifor R. Williams ◽  
Robert Hasserjian ◽  
Chirayu Udomsakdi ◽  
Shannon M. McGrath ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Transgenic Animals ◽  
Myeloid Lineage ◽  
Protein Tyrosine

Abstract The TEL/PDGFβR fusion protein is expressed as the consequence of a recurring t(5;12) translocation associated with chronic myelomonocytic leukemia (CMML). Unlike other activated protein tyrosine kinases associated with hematopoietic malignancies, TEL/PDGFβR is invariably associated with a myeloid leukemia phenotype in humans. To test the transforming properties of TEL/PDGFβR in vivo, and to analyze the basis for myeloid lineage specificity in humans, we constructed transgenic mice with TEL/PDGFβR expression driven by a lymphoid-specific immunoglobulin enhancer-promoter cassette. These mice developed lymphoblastic lymphomas of both T and B lineage, demonstrating that TEL/PDGFβR is a transforming protein in vivo, and that the transforming ability of this fusion is not inherently restricted to the myeloid lineage. Treatment of TEL/PDGFβR transgenic animals with a protein tyrosine kinase inhibitor with in vitro activity against PDGFβR (CGP57148) resulted in suppression of disease and a prolongation of survival. A therapeutic benefit was apparent both in animals treated before the development of overt clonal disease and in animals transplanted with clonal tumor cells. These results suggest that small-molecule tyrosine kinase inhibitors may be effective treatment for activated tyrosine kinase–mediated malignancies both early in the course of disease and after the development of additional transforming mutations.

Activation of tyrosine kinases in H2O2-induced contraction in pulmonary artery

1997 ◽  
Vol 272 (6) ◽  
pp. H2686-H2692 ◽  
Author(s):  
N. Jin ◽  
R. A. Rhoades
Keyword(s):  
Smooth Muscle ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Pulmonary Arteries ◽  
Smooth Muscle Contraction ◽  
Muscle Dysfunction ◽  
Calmodulin Antagonist ◽  
Smooth Muscle Dysfunction

Hydrogen peroxide (H2O2) is an important reactive oxygen species implicated in lung vascular constriction and injury. The purpose of this study was to investigate the role of tyrosine kinases in H2O2-induced vascular contraction and dysfunction. In our study, H2O2 (200 microM) caused an initial transient contraction followed by a strong, sustained contraction in isolated rat pulmonary arteries. Genistein, a tyrosine kinase inhibitor, attenuated both the initial and the sustained contractions. Aminogenistein and tyrphostin 51, specific inhibitors of tyrosine kinases, had the same effects as genistein. Exposure of pulmonary arteries to H2O2 for 1 h caused a significant reduction in the contractile response to KCl or phenylephrine and in the vasodilatory response to acetylcholine (smooth muscle dysfunction). Although tyrosine kinase inhibitors significantly blocked contractions induced by H2O2, pretreatment of pulmonary arteries with these inhibitors before H2O2 exposure did not prevent the decreases in responses to KCl, phenylephrine, or acetylcholine. Removal of extracellular Ca2+ and depletion of intracellular Ca2+ pools by ryanodine or thapsigargin did not inhibit the initial and sustained contractions in response to H2O2. W-7, a calmodulin antagonist, or ML-9, a myosin light chain kinase inhibitor, significantly inhibited the sustained contractions but did not prevent smooth muscle dysfunction induced by H2O2. These data show that 1) exposure to H2O2 causes smooth muscle contractions and dysfunction in isolated pulmonary arteries and 2) activation of tyrosine kinases mediates H2O2-induced contractions; however, tyrosine kinases do not appear to be involved in H2O2-induced inhibition of arterial responses to vasoactive substances. These data suggest that different signaling pathways and mechanisms are involved in H2O2-induced smooth muscle contraction and dysfunction.

scholarly journals Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation

2020 ◽  
Vol 41 (41) ◽  
pp. 4037-4046 ◽  
Author(s):  
Lars Wallentin ◽  
Johan Lindbäck ◽  
Niclas Eriksson ◽  
Ziad Hijazi ◽  
John W Eikelboom ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Cardiovascular Disease ◽  
Angiotensin Converting Enzyme ◽  
Association Studies ◽  
Cell Surface Receptor ◽  
Genome Wide Association Studies ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Cellular Expression ◽  
Male Sex

Abstract Aims The global COVID-19 pandemic is caused by the SARS-CoV-2 virus entering human cells using angiotensin-converting enzyme 2 (ACE2) as a cell surface receptor. ACE2 is shed to the circulation, and a higher plasma level of soluble ACE2 (sACE2) might reflect a higher cellular expression of ACE2. The present study explored the associations between sACE2 and clinical factors, cardiovascular biomarkers, and genetic variability. Methods and results Plasma and DNA samples were obtained from two international cohorts of elderly patients with atrial fibrillation (n = 3999 and n = 1088). The sACE2 protein level was measured by the Olink Proteomics® Multiplex CVD II96 × 96 panel. Levels of the biomarkers high-sensitive cardiac troponin T (hs-cTnT), N-terminal probrain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), C-reactive protein, interleukin-6, D-dimer, and cystatin-C were determined by immunoassays. Genome-wide association studies were performed by Illumina chips. Higher levels of sACE2 were statistically significantly associated with male sex, cardiovascular disease, diabetes, and older age. The sACE2 level was most strongly associated with the levels of GDF-15, NT-proBNP, and hs-cTnT. When adjusting for these biomarkers, only male sex remained associated with sACE2. We found no statistically significant genetic regulation of the sACE2 level. Conclusions Male sex and clinical or biomarker indicators of biological ageing, cardiovascular disease, and diabetes are associated with higher sACE2 levels. The levels of GDF-15 and NT-proBNP, which are associated both with the sACE2 level and a higher risk for mortality and cardiovascular disease, might contribute to better identification of risk for severe COVID-19 infection.

Are tyrosine kinases involved in mediating contraction-stimulated muscle glucose transport?

2006 ◽  
Vol 290 (1) ◽  
pp. E123-E128 ◽  
Author(s):  
David C. Wright ◽  
Paige C. Geiger ◽  
Dong-Ho Han ◽  
John O. Holloszy
Keyword(s):  
Protein Kinase ◽  
Cell Surface ◽  
Tyrosine Kinase ◽  
Glucose Transport ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Muscle Contractions ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein

Muscle contractions and insulin stimulate glucose transport into muscle by separate pathways. The contraction-mediated increase in glucose transport is mediated by two mechanisms, one involves the activation of 5′-AMP-activated protein kinase (AMPK) and the other involves the activation of calcium/calmodulin-dependent protein kinase II (CAMKII). The steps leading from the activation of AMPK and CAMKII to the translocation of GLUT4 to the cell surface have not been identified. Studies with the use of the tyrosine kinase inhibitor genistein suggest that one or more tyrosine kinases could be involved in contraction-stimulated glucose transport. The purpose of the present study was to determine the involvement of tyrosine kinases in contraction-stimulated glucose transport in rat soleus and epitrochlearis muscles. Contraction-stimulated glucose transport was completely prevented by pretreatment with genistein (100 μM) and the related compound butein (100 μM). However, the structurally distinct tyrosine kinase inhibitors 4-amino-5-(4-chlorophenyl)-7-( t-butyl)pyrazolo[3,4-d]pyridine and herbimycin did not reduce contraction-stimulated glucose transport. Furthermore, genistein and butein inhibited glucose transport even when muscles were exposed to these compounds after being stimulated to contract. Muscle contractions did not result in increases in tyrosine phosphorylation of proteins such as proline-rich tyrosine kinase and SRC. These results provide evidence that tyrosine kinases do not mediate contraction-stimulated glucose transport and that the inhibitory effects of genistein on glucose transport result from direct inhibition of the glucose transporters at the cell surface.

scholarly journals Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Keiji Kuba ◽  
Tomokazu Yamaguchi ◽  
Josef M. Penninger
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Neutralizing Antibodies ◽  
Cell Entry ◽  
Converting Enzyme ◽  
Sars Coronavirus ◽  
Angiotensin Converting Enzyme 2 ◽  
Infected People ◽  
Critical Attention ◽  
Novel Coronavirus

Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.

scholarly journals Naturally mutated spike proteins of SARS-CoV-2 variants show differential levels of cell entry

2020 ◽  
Author(s):  
Seiya Ozono ◽  
Yanzhao Zhang ◽  
Hirotaka Ode ◽  
Toong Seng Tan ◽  
Kazuo Imai ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Causative Agent ◽  
Cell Entry ◽  
Viral Infectivity ◽  
Converting Enzyme ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Naturally Occurring ◽  
Spike Proteins

AbstractThe causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is steadily mutating during continuous transmission among humans. Such mutations can occur in the spike (S) protein that binds to the angiotensin-converting enzyme-2 (ACE2) receptor and is cleaved by transmembrane protease serine 2 (TMPRSS2). However, whether S mutations affect SARS-CoV-2 infectivity remains unknown. Here, we show that naturally occurring S mutations can reduce or enhance cell entry via ACE2 and TMPRSS2. A SARS-CoV-2 S-pseudotyped lentivirus exhibits substantially lower entry than SARS-CoV S. Among S variants, the D614G mutant shows the highest cell entry, as supported by structural observations. Nevertheless, the D614G mutant remains susceptible to neutralization by antisera against prototypic viruses. Taken together, these data indicate that the D614G mutation enhances viral infectivity while maintaining neutralization susceptibility.

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.

scholarly journals Estrogen regulates the expression of SARS-CoV-2 receptor ACE2 in differentiated airway epithelial cells

2020 ◽  
Vol 318 (6) ◽  
pp. L1280-L1281 ◽  
Author(s):  
Kimberly E. Stelzig ◽  
Fabrizio Canepa-Escaro ◽  
Marta Schiliro ◽  
Sergejs Berdnikovs ◽  
Y. S. Prakash ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Epithelial Cells ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Sex Steroids ◽  
Airway Epithelial Cells ◽  
Cell Entry ◽  
Airway Epithelial ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2

There is marked sexual dimorphism in the current coronavirus disease 2019 (COVID-19) pandemic. Here we report that estrogen can regulate the expression of angiotensin-converting enzyme 2 (ACE2), a key component for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry, in differentiated airway epithelial cells. Further studies are required to elucidate the mechanisms by which sex steroids regulate SARS-CoV-2 infectivity.

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