scholarly journals Acute SARS-CoV-2 infection in pregnancy is associated with placental ACE-2 shedding

2021 ◽  
Author(s):  
Elizabeth S Taglauer ◽  
Elisha M Wachman ◽  
Lillian Juttukonda ◽  
Timothy Klouda ◽  
Jiwon Kim ◽  
...  
Keyword(s):  
Cell Surface ◽  
Angiotensin Converting Enzyme ◽  
Human Placenta ◽  
Maternal Serum ◽  
Converting Enzyme ◽  
Serum Samples ◽  
Parallel Increase ◽  
Cleavage Enzyme ◽  
Maternal Fetal Interface ◽  
In Pregnancy

Human placental tissues have variable rates of SARS-CoV-2 invasion resulting in consistently low rates of fetal transmission suggesting a unique physiologic blockade against SARS-CoV-2. Angiotensin-converting enzyme (ACE)-2, the main receptor for SARS-CoV-2, is expressed as cell surface and soluble forms regulated by a metalloprotease cleavage enzyme, ADAM17. ACE-2 is expressed in the human placenta, but the regulation of placental ACE-2 expression in relation to timing of maternal SARS-CoV-2 infection in pregnancy is not well understood. In this study, we evaluated ACE-2 expression, ADAM17 activity and serum ACE-2 abundance in a cohort of matched villous placental and maternal serum samples from Control pregnancies (SARS-CoV-2 negative, n=8) and pregnancies affected by symptomatic maternal SARS-CoV-2 infections in the 2nd trimester (2ndTri COVID, n=8) and 3rd trimester (3rdTri COVID, n=8). In 3rdTri COVID as compared to control and 2ndTri-COVID villous placental tissues ACE-2 mRNA expression was remarkably elevated, however, ACE-2 protein expression was significantly decreased with a parallel increase in ADAM17 activity. Soluble ACE-2 was also significantly increased in the maternal serum from 3rdTri COVID infections as compared to control and 2ndTri-COVID pregnancies. These data suggest that in acute maternal SARS-CoV-2 infections, decreased placental ACE-2 protein may be the result of ACE-2 shedding. Overall, this work highlights the importance of ACE-2 for ongoing studies on SARS-CoV-2 responses at the maternal-fetal interface.

scholarly journals ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Sally Badawi ◽  
Bassam R. Ali
Keyword(s):  
Cell Surface ◽  
Angiotensin Converting Enzyme ◽  
The Novel ◽  
Converting Enzyme ◽  
Post Translational Modifications ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Attachment ◽  
Novel Coronavirus ◽  
Effective Medication ◽  
Potential Use

AbstractWith the emergence of the novel coronavirus SARS-CoV-2 since December 2019, more than 65 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases, leading to over 1.5 million deaths globally. Despite the collaborative and concerted research efforts that have been made, no effective medication for COVID-19 (coronavirus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in the human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2–based therapeutic strategies have aimed to tackle the virus through the use of angiotensin-converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2, which does not directly aim to reduce its membrane availability. However, through this review, we present a different perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, and shedding and cellular trafficking pathways including the internalization are not well elucidated in literature. Therefore, we hereby present an overview of the fate of newly synthesized ACE2, its post translational modifications, and what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Moreover, an extensive understanding of these processes is necessarily required to evaluate the potential use of ACE2 as a credible therapeutic target.

Increasing exposure to angiotensin-converting enzyme inhibitors in pregnancy

2008 ◽  
Vol 198 (3) ◽  
pp. 291.e1-291.e5 ◽  
Author(s):  
Michael E. Bowen ◽  
Wayne A. Ray ◽  
Patrick G. Arbogast ◽  
Hua Ding ◽  
William O. Cooper
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Enzyme Inhibitors ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
In Pregnancy

Roles of the juxtamembrane and extracellular domains of angiotensin-converting enzyme in ectodomain shedding

2001 ◽  
Vol 358 (1) ◽  
pp. 185-192 ◽  
Author(s):  
Susan PANG ◽  
Anthony J. CHUBB ◽  
Sylva L. U. SCHWAGER ◽  
Mario R. W. EHLERS ◽  
Edward D. STURROCK ◽  
...  
Keyword(s):  
Cell Surface ◽  
Angiotensin Converting Enzyme ◽  
Active Form ◽  
Ectodomain Shedding ◽  
Converting Enzyme ◽  
Critical Determinant ◽  
Terminal Domain ◽  
Cytosolic Domains ◽  
Identical Manner ◽  
Substrate Proteins

Angiotensin-converting enzyme (ACE) is one of a growing number of integral membrane proteins that is shed from the cell surface through proteolytic cleavage by a secretase. To investigate the requirements for ectodomain shedding, we replaced the glycosylphosphatidylinositol addition sequence in membrane dipeptidase (MDP) - a membrane protein that is not shed - with the juxtamembrane stalk, transmembrane (TM) and cytosolic domains of ACE. The resulting construct, MDP–STMACE, was targeted to the cell surface in a glycosylated and enzymically active form, and was shed into the medium. The site of cleavage in MDP–STMACE was identified by MS as the Arg374-Ser375 bond, corresponding to the Arg1203-Ser1204 secretase cleavage site in somatic ACE. The release of MDP–STMACE and ACE from the cells was inhibited in an identical manner by batimastat and two other hydroxamic acid-based zinc metallosecretase inhibitors. In contrast, a construct lacking the juxtamembrane stalk, MDP–TMACE, although expressed at the cell surface in an enzymically active form, was not shed, implying that the juxtamembrane stalk is the critical determinant of shedding. However, an additional construct, ACEΔC, in which the N-terminal domain of somatic ACE was fused to the stalk, TM and cytosolic domains, was also not shed, despite the presence of a cleavable stalk, implying that in contrast with the C-terminal domain, the N-terminal domain lacks a signal required for shedding. These data are discussed in the context of two classes of secretases that differ in their requirements for recognition of substrate proteins.

scholarly journals Functional Complexes of Angiotensin-Converting Enzyme 2 and Renin-Angiotensin System Receptors: Expression in Adult but Not Fetal Lung Tissue

2020 ◽  
Vol 21 (24) ◽  
pp. 9602
Author(s):  
Rafael Franco ◽  
Alejandro Lillo ◽  
Rafael Rivas-Santisteban ◽  
Ana I. Rodríguez-Pérez ◽  
Irene Reyes-Resina ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cell Surface ◽  
Angiotensin Converting Enzyme ◽  
Ligand Binding ◽  
Renin Angiotensin System ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2

Angiotensin-converting enzyme 2 (ACE2) is a membrane peptidase and a component of the renin-angiotensin system (RAS) that has been found in cells of all organs, including the lungs. While ACE2 has been identified as the receptor for severe acute respiratory syndrome (SARS) coronaviruses, the mechanism underlying cell entry remains unknown. Human immunodeficiency virus infects target cells via CXC chemokine receptor 4 (CXCR4)-mediated endocytosis. Furthermore, CXCR4 interacts with dipeptidyl peptidase-4 (CD26/DPPIV), an enzyme that cleaves CXCL12/SDF-1, which is the chemokine that activates this receptor. By analogy, we hypothesized that ACE2 might also be capable of interactions with RAS-associated G-protein coupled receptors. Using resonance energy transfer and cAMP and mitogen-activated protein kinase signaling assays, we found that human ACE2 interacts with RAS-related receptors, namely the angiotensin II type 1 receptor (AT1R), the angiotensin II type 2 receptor (AT2R), and the MAS1 oncogene receptor (MasR). Although these interactions led to various alterations of signal transduction, but, more importantly, ligand binding to AT1R resulted in the downregulation of ACE2 cell surface expression, while ligand binding to AT2R, but not to MasR, resulted in upregulation of ACE2 cell surface expression. Proximity ligation assays performed in situ revealed macromolecular complexes containing ACE2 and AT1R, AT2R or MasR in adult but not fetal mouse lung tissue. These findings highlight the relevance of RAS in SARS-CoV-2 infection and the role of ACE2-containing complexes as potential therapeutic targets.

scholarly journals Angiotensin Converting Enzyme 2 (ACE2) in Pregnancy: Preeclampsia and Small for Gestational Age

2020 ◽  
Vol 11 ◽  
Author(s):  
Sonia Tamanna ◽  
Vicki L. Clifton ◽  
Kym Rae ◽  
Dirk F. van Helden ◽  
Eugenie R. Lumbers ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
In Pregnancy
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