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Open accessJournal ArticleDOI: 10.1111/JCMM.16310

Pulmonary, cardiac and renal distribution of ACE2, furin, TMPRSS2 and ADAM17 in rats with heart failure: Potential implication for COVID-19 disease.

04 Mar 2021-Journal of Cellular and Molecular Medicine (John Wiley & Sons, Ltd)-Vol. 25, Iss: 8, pp 3840-3855
Abstract: Congestive heart failure (CHF) is often associated with kidney and pulmonary dysfunction. Activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid sodium retention, cardiac hypertrophy and oedema formation, including lung congestion. While the status of the classic components of RAAS such as renin, angiotensin converting enzyme (ACE), angiotensin II (Ang II) and angiotensin II receptor AT-1 is well studied in CHF, the expression of angiotensin converting enzyme-2 (ACE2), a key enzyme of angiotensin 1-7 (Ang 1-7) generation in the pulmonary, cardiac and renal systems has not been studied thoroughly in this clinical setting. This issue is of a special interest as Ang 1-7 counterbalance the vasoconstrictory, pro-inflammatory and pro-proliferative actions of Ang II. Furthermore, CHF predisposes to COVID-19 disease severity, while ACE2 also serves as the binding domain of SARS-CoV-2 in human host-cells, and acts in concert with furin, an important enzyme in the synthesis of BNP in CHF, in permeating viral functionality along TMPRSST2. ADAM17 governs ACE2 shedding from cell membranes. Therefore, the present study was designed to investigate the expression of ACE2, furin, TMPRSS2 and ADAM17 in the lung, heart and kidneys of rats with CHF to understand the exaggerated susceptibility of clinical CHF to COVID-19 disease. Heart failure was induced in male Sprague Dawley rats by the creation of a surgical aorto-caval fistula. Sham-operated rats served as controls. One week after surgery, the animals were subdivided into compensated and decompensated CHF according to urinary sodium excretion. Both groups and their controls were sacrificed, and their hearts, lungs and kidneys were harvested for assessment of tissue remodelling and ACE2, furin, TMPRSS2 and ADAM17 immunoreactivity, expression and immunohistochemical staining. ACE2 immunoreactivity and mRNA levels increased in pulmonary, cardiac and renal tissues of compensated, but not in decompensated CHF. Furin immunoreactivity was increased in both compensated and decompensated CHF in the pulmonary, cardiac tissues and renal cortex but not in the medulla. Interestingly, both the expression and abundance of pulmonary, cardiac and renal TMPRSS2 decreased in CHF in correlation with the severity of the disease. Pulmonary, cardiac and renal ADAM17 mRNA levels were also downregulated in decompensated CHF. Circulating furin levels increased in proportion to CHF severity, whereas plasma ACE2 remained unchanged. In summary, ACE2 and furin are overexpressed in the pulmonary, cardiac and renal tissues of compensated and to a lesser extent of decompensated CHF as compared with their sham controls. The increased expression of the ACE2 in heart failure may serve as a compensatory mechanism, counterbalancing the over-activity of the deleterious isoform, ACE. Downregulated ADAM17 might enhance membranal ACE2 in COVID-19 disease, whereas the suppression of TMPRSS2 in CHF argues against its involvement in the exaggerated susceptibility of CHF patients to SARS-CoV2.

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Topics: Angiotensin II (58%), Angiotensin-converting enzyme 2 (58%), Heart failure (58%) ... read more
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7 results found


Open accessJournal ArticleDOI: 10.3390/JCM10061200
Abstract: Membrane-bound angiotensin converting enzyme (ACE) 2 serves as a receptor for the Sars-CoV-2 spike protein, permitting viral attachment to target host cells. The COVID-19 pandemic brought into light ACE2, its principal product angiotensin (Ang) 1-7, and the G protein-coupled receptor for the heptapeptide (MasR), which together form a still under-recognized arm of the renin-angiotensin system (RAS). This axis counteracts vasoconstriction, inflammation and fibrosis, generated by the more familiar deleterious arm of RAS, including ACE, Ang II and the ang II type 1 receptor (AT1R). The COVID-19 disease is characterized by the depletion of ACE2 and Ang-(1-7), conceivably playing a central role in the devastating cytokine storm that characterizes this disorder. ACE2 repletion and the administration of Ang-(1-7) constitute the therapeutic options currently tested in the management of severe COVID-19 disease cases. Based on their beneficial effects, both ACE2 and Ang-(1-7) have also been suggested to slow the progression of experimental diabetic and hypertensive chronic kidney disease (CKD). Herein, we report a further step undertaken recently, utilizing this type of intervention in the management of evolving acute kidney injury (AKI), with the expectation of renal vasodilation and the attenuation of oxidative stress, inflammation, renal parenchymal damage and subsequent fibrosis. Most outcomes indicate that triggering the ACE2/Ang-(1-7)/MasR axis may be renoprotective in the setup of AKI. Yet, there is contradicting evidence that under certain conditions it may accelerate renal damage in CKD and AKI. The nature of these conflicting outcomes requires further elucidation.

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4 Citations


Open accessJournal ArticleDOI: 10.1007/S11154-021-09663-Z
Joshua R Cook1, John Ausiello1Institutions (1)
Abstract: SARS-CoV-2, the virus responsible for COVID-19, uses angiotensin converting enzyme 2 (ACE2) as its primary cell-surface receptor. ACE2 is a key enzyme in the counter-regulatory pathway of the broader renin-angiotensin system (RAS) that has been implicated in a broad array of human pathology. The RAS is composed of two competing pathways that work in opposition to each other: the "conventional" arm involving angiotensin converting enzyme (ACE) generating angiotensin-2 and the more recently identified ACE2 pathway that generates angiotensin (1-7). Following the original SARS pandemic, additional studies suggested that coronaviral binding to ACE2 resulted in downregulation of the membrane-bound enzyme. Given the similarities between the two viruses, many have posited a similar process with SARS-CoV-2. Proponents of this ACE2 deficiency model argue that downregulation of ACE2 limits its enzymatic function, thereby skewing the delicate balance between the two competing arms of the RAS. In this review we critically examine this model. The available data remain incomplete but are consistent with the possibility that the broad multisystem dysfunction of COVID-19 is due in large part to functional ACE2 deficiency leading to angiotensin imbalance with consequent immune dysregulation and endothelial cell dysfunction.

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3 Citations


Open accessJournal ArticleDOI: 10.3390/JCM10173885
Abstract: Angiotensin (ANG)-converting enzyme (ACE2) is an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). ACE2 also contributes to a deviation of the lung renin-angiotensin system (RAS) towards its counter-regulatory axis, thus transforming harmful ANG II to protective ANG (1-7). Based on this purported ACE2 double function, it has been put forward that the benefit from ACE2 upregulation with renin-angiotensin-aldosterone system inhibitors (RAASi) counterbalances COVID-19 risks due to counter-regulatory RAS axis amplification. In this manuscript we discuss the relationship between ACE2 expression and function in the lungs and other organs and COVID-19 severity. Recent data suggested that the involvement of ACE2 in the lung counter-regulatory RAS axis is limited. In this setting, an augmentation of ACE2 expression and/or a dissociation of ACE2 from the ANG (1-7)/Mas pathways that leaves unopposed the ACE2 function, the SARS-CoV-2 entry receptor, predisposes to more severe disease and it appears to often occur in the relevant risk factors. Further, the effect of RAASi on ACE2 expression and on COVID-19 severity and the overall clinical implications are discussed.

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1 Citations


Open accessJournal ArticleDOI: 10.1093/CID/CIAB840
Abstract: Observations of vertical transmission of SARS-CoV-2 infection from mother to foetus have recently been described in the literature. However, the consequences of such transmission, whether foetal or neonatal, are poorly understood. From a case of in utero foetal death at 24 +2 weeks of gestation that occurred seven days after the diagnosis of symptomatic SARS-CoV-2 infection in the mother, we isolated the incriminating virus by immunochemistry and molecular techniques in several foetal tissues, with a variant analysis of the SARS-CoV-2 genome. Moreover, the foetal demise could be explained by the presence of placental histological lesions, such as histiocytic intervillositis and trophoblastic necrosis, in addition to foetal tissue damage. We observed mild foetal growth retardation and visceral damage to the liver, causing hepatocellular damage and haemosiderosis. To the best of our knowledge, this is the first report in the literature of foetal demise secondary to maternal-foetal transmission of SARS-CoV-2 with a congenital infection and a pathological description of placental and foetal tissue damage. SARS-CoV-2 was identified in both specimens by three independent techniques (immunochemistry, RT-qPCR and RT-dPCR). Furthermore, the incriminating variant has been identified.

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Open accessPosted ContentDOI: 10.1101/2021.10.19.465025
20 Oct 2021-bioRxiv
Abstract: Angiotensin-converting enzyme 2 (ACE2) is the established cellular receptor for SARS-CoV-2. However, it is unclear whether ACE1 inhibitors (e.g., lisinopril) or angiotensin receptor blockers (e.g., losartan) alter tissue ACE2 expression. This study sought to determine whether lisinopril or losartan, as monotherapies or in combination, change tissue levels of ACE2 in healthy male and female mice. Mice were treated for 21 days with drinking water containing lisinopril (10 mg/kg/day), losartan (10 mg/kg/day), or both. A control group was given water without drug. ACE2 protein index, the ratio of ACE2 protein to total protein, was determined on tissues from the small intestine, lung, kidney, and brain. Oral lisinopril increased ACE2 protein index across all tissues (p

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Topics: Losartan (60%), Lisinopril (60%)

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60 results found


Open accessJournal ArticleDOI: 10.1038/S41586-020-2012-7
Peng Zhou1, Xing-Lou Yang1, Xian Guang Wang2, Ben Hu1  +25 moreInstitutions (3)
03 Feb 2020-Nature
Abstract: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1–4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV. Characterization of full-length genome sequences from patients infected with a new coronavirus (2019-nCoV) shows that the sequences are nearly identical and indicates that the virus is related to a bat coronavirus.

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Topics: Coronavirus (67%), Betacoronavirus (54%), Deltacoronavirus (51%) ... read more

12,056 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2020.02.058
16 Apr 2020-Cell
Abstract: The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.

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Topics: Ectodomain (56%), Viral entry (55%), Epitope (53%) ... read more

4,968 Citations


Open accessJournal ArticleDOI: 10.1038/NATURE02145
Wenhui Li1, Michael Moore1, Natalya Vasilieva2, Jianhua Sui3  +8 moreInstitutions (5)
27 Nov 2003-Nature
Abstract: Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells Together our data indicate that ACE2 is a functional receptor for SARS-CoV

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Topics: Coronavirus (63%), Vero cell (60%), Severe acute respiratory syndrome (53%) ... read more

4,123 Citations


Open accessBook
15 Dec 2005-
Topics: Heart failure (66%)

3,609 Citations


Open accessJournal ArticleDOI: 10.1002/PATH.1570
Inge Hamming1, Wim Timens1, Marian Bulthuis1, A. T. Lely1  +2 moreInstitutions (1)
Abstract: Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS-CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS-CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations.

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Topics: Severe acute respiratory syndrome (59%), Coronavirus (56%), Pathogenesis (51%) ... read more

3,486 Citations