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Id Subject Object Predicate Lexical cue
T1 0-27 Sentence denotes ACE2 receptor polymorphism:
T2 28-121 Sentence denotes Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome
T3 123-131 Sentence denotes Abstract
T4 132-340 Sentence denotes The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged in Chinese people in December 2019 and has currently spread worldwide causing the COVID-19 pandemic with more than 150,000 deaths.
T5 341-625 Sentence denotes In order for a SARS-CoV like virus circulating in wild life for a very long time to infect the index case-patient, a number of conditions must be met, foremost among which is the encounter with humans and the presence in homo sapiens of a cellular receptor allowing the virus to bind.
T6 626-743 Sentence denotes Recently it was shown that the SARS-CoV-2 spike protein, binds to the human angiotensin I converting enzyme 2 (ACE2).
T7 744-898 Sentence denotes This molecule is a peptidase expressed at the surface of lung epithelial cells and other tissues, that regulates the renin-angiotensin-aldosterone system.
T8 899-979 Sentence denotes Humans are not equal with respect to the expression levels of the cellular ACE2.
T9 980-1054 Sentence denotes Moreover, ACE2 polymorphisms were recently described in human populations.
T10 1055-1250 Sentence denotes Here we review the most recent evidence that ACE2 expression and/or polymorphism could influence both the susceptibility of people to SARS-CoV-2 infection and the outcome of the COVID-19 disease.
T11 1251-1565 Sentence denotes Further exploration of the relationship between the virus, the peptidase function of ACE2 and the levels of angiotensin II in SARS-CoV-2 infected patients should help to better understand the pathophysiology of the disease and the multi-organ failures observed in severe COVID-19 cases, particularly heart failure.
T12 1567-1579 Sentence denotes Introduction
T13 1580-1704 Sentence denotes Over the past 20 years, seven coronaviruses responsible for more or less severe respiratory diseases have emerged in humans.
T14 1705-2449 Sentence denotes Several of them, including SARS-CoV-2 (a Betacoronavirus lineage b/Sarbecovirus), can cause patients lung injury and sometimes multi-organ failure with adverse myocardial remodeling, myocardial stress, and cardiomyopathy.1 , 2 Recently, SARS-CoV-2 was reported to be a human angiotensin I converting enzyme 2 (ACE2)-tropic virus3 , 4 able to bind the alveolar pneumocytes which express ACE2 at their surface.5 , 6 Yet, in humans the ACE2 mRNAs were found expressed in virtually all organs including the heart, blood vessels, kidney and testis, opening the possibility for this virus to infect other tissues beside lung.7 , 8 ACE2 is a known peptidase that regulates the renin-angioten-aldosterone system (RAAS), thus controlling blood pressure.
T15 2450-2626 Sentence denotes Therefore, it is not surprising that initials reports suggested that hypertension, diabetes and cardiovascular diseases were the most frequent comorbidity in COVID-19 disease.9
T16 2628-2651 Sentence denotes The human coronaviruses
T17 2652-3785 Sentence denotes Coronaviruses (CoV) circulate in bats and generally pass over an intermediate animal host before crossing species barrier to infect humans.10 Different species of bats in China carry genetically diverse coronaviruses, some of which are direct ancestors of SARS-CoV.11, 12, 13 Indeed, the first SARS-CoV that caused a human outbreak derived from SARS-like CoV circulating in Chinese horseshoe Rhinolophus bats which apparently adapted to wild Himalayan palm-civet before spreading in humans.14 The MERS-CoV originated from a Pipistrellus bat CoV and was probably transmitted to humans through contact with infected camels.15, 16, 17 Soon after the first outbreak of SARS-CoV-2 in humans, it was reported that this new virus was related to a bat-borne coronavirus (BatCoV RaTG13) present in the Rhinolophus affinis bat species.18 The identification of an intermediate animal hosts has been the subject of intense research and it was claimed that a pangolin (Manis javanica) was the intermediate host for SARS-CoV-2.19 The SARS-CoV-2 receptor ACE2 from bat and pangolin and several other species, were found to resemble that of human.20
T18 3786-4005 Sentence denotes Before 2003, although human coronavirus 229E (HCoV-229E) (Alphacoronavirus) and HCoV-OC43 (Betacoronavirus lineage a) described in the 1960s were known to be agents of respiratory infections, they lent little attention.
T19 4006-4175 Sentence denotes In the early 2000s, two other coronaviruses responsible for similar diseases were identified, the HCoV-NL63 (Alphacoronavirus) and HCoV-HKU1 (Betacoronavirus lineage a).
T20 4176-4308 Sentence denotes Even if the health authorities pay little attention to these viruses, sometimes they can cause deaths in people with fragile health.
T21 4309-4488 Sentence denotes A study in Switzerland reported that among 279 subjects who had bronchoalveolar lavage for investigation of respiratory symptoms, 29 were tested positive for HCoV (detection rate:
T22 4489-5269 Sentence denotes 10.4%).21 A large-scale polymerase chain reaction (PCR) screening of 11,661 nasal samples from European patients with respiratory disease, found 35 HCoV-229E (0.30%), 61 HCoV-HKU1 (0.52%), 75 HCoV-NL63 (0.64%), and 111 HCoV-OC43 (0.85%).22 A similar study in Africa on 5573 nasal samples from child hospitalized for pneumonia found 114 HCoV-229E (2.05%), 163 HCoV-NL63 (2.93%), and 111 HCoV-OC43 (1.99%).23 Two Chinese studies involving almost 25,000 throat and nasal swab samples from patients with acute respiratory tract infections revealed 114 HCoV-229E (0.37%–0.57%), 61 HCoV-HKU1 (0.18%–0.33%), 104 HCoV-NL63 (0.33%–0.52%), and 523 HCoV-OC43 (1.36%–3.04%), respectively.24 , 25 The fatality rate of the coronaviruses causing the common winter cold was estimated 0.5%–1.5%.26
T23 5270-5643 Sentence denotes Coronaviruses strongly gained in notoriety when SARS-CoV (Betacoronavirus lineage b) emerged in China in March 2003 and was proven responsible for the severe acute respiratory syndrome (SARS) outbreak in humans.27 The SARS-CoV adapted to humans and became able to spread from person-to-person leading to a fatality rate of 9.6% in infected patients, causing global concern.
T24 5644-5778 Sentence denotes The Middle East Respiratory Syndrome (MERS) caused by the MERS-CoV (Betacoronavirus lineage 2c), was reported in Saudi Arabia in 2012.
T25 5779-6268 Sentence denotes This epidemic which has been one of the least deadly in absolute number of deaths, was the one which has created the most fears in health authorities and the most important panic in the populations due to its high fatality rate (case fatality rate of 34.7%).28 The SARS-CoV-2 that emerged in China at the end of 2019, is responsible for respiratory infections including pneumonia with a mortality rate estimated about 1%–2.5%,2 increasing with age and the existence of underlying diseases.
T26 6269-6468 Sentence denotes Under chest computerized tomography (CT) scans, the majority of patients show bilateral ground glass-like opacities and subsegmental areas of consolidation indicative of SARS-CoV-2 induced pneumonia.
T27 6470-6533 Sentence denotes The MERS-CoV, SARS-CoV, SARS-CoV-2 and their cellular receptors
T28 6534-7525 Sentence denotes Already for SARS-CoV, it was demonstrated that this virus used the angiotensin I converting enzyme 2 (ACE2) to enter human cells.29 The novel Betacoronavirus SARS-CoV-2 (formerly 2019-nCoV), that cause COVID-19 disease, has 79.5% nucleotide identity with SARS-CoV.1 It is worth noting that HCoV-NL63, SARS-CoV and SARS-CoV-2 spike proteins bind ACE230 expressed at high levels in type I and II alveolar cells in the lung, whereas MERS-CoV bind the dipeptidyl peptidase 4 (DPP4)/CD26), a multifunctional serine peptidase known involved in T cell activation.31 The analysis of SARS-CoV-2 spike (S) protein and ACE2 three-dimensional (3-D) structures allowed identification of regions in the peptidase domain of ACE2 required for viral spike binding.3 Three very elegant papers published in the recent weeks characterized SARS-CoV-2 entry in target cells through interactions with ACE2 and serine protease TMPRSS2 priming as well as the 3-D structures involved in these interactions.3 , 32 , 33
T29 7526-8596 Sentence denotes The human monocarboxypeptidase ACE-2 was originally cloned from human heart failure and lymphoma cDNA libraries.7 Although the ACE2 gene is usually considered silent in immune cells, the expression of ACE2 mRNAs was reported in a subset of CD14+ CD16-human monocytes.34 ACE2 is also expressed by enterocytes of the small intestine and expected to regulate the expression of the gut antimicrobial peptides.35 Moreover, this peptidase is also present on the arterial and venous endothelial cells, and arterial smooth muscle.36 In normal human lung, the ACE2 protein is found on type I and II alveolar epithelial lung cells.37 High expression of ACE2 was also reported on the epithelial cells of oral mucosa.38 Single-cell RNA-seq analysis indicated that Asian men have a higher ACE2 mRNA expression in lung than women and that Asian people express higher amount of ACE2 than Caucasian and African American populations,39 but this observation remains controversial.40 Until recently, the genetic basis of ACE2 expression in different populations remained largely unknown.41
T30 8598-8625 Sentence denotes ACE2 structure and function
T31 8626-8691 Sentence denotes The ACE2 gene span 39.98 kb of genomic DNA and contains 18 exons.
T32 8692-9707 Sentence denotes It maps to chromosome X at position Xp22.8 It encodes a type I cell-surface glycoprotein of about 100 kDa, composed by 805 amino acids and characterized by a N-terminal signal peptide of 17 amino acid residues, a peptidase domain (PD) (residues 19–615) with its HEXXH zinc binding metalloprotease motif, a C-terminal Collectrin (a regulator of renal amino acid transport and insulin)-like domain (CLD) (residues 616–768) that includes a ferredoxin-like fold “Neck” domain (615–726), that end with an hydrophobic transmembrane hydrophobic helix region of 22 amino acid residues followed by an intracellular segment of 43 amino acid residues.7 , 42 The histidine motif HEXXH identified as an important component in a wide variety of zinc-dependent metalloproteases consists of five residues, the first histidine followed by glutamic acid being conserved, then the two variable amino acids and a final histidine.43 Crystal structure analysis have suggested the presence of several hinge regions and N-glycosylations.44
T33 9708-9790 Sentence denotes ACE2 belongs to the family of ACE members which have a wider tissues distribution.
T34 9791-9942 Sentence denotes The juxtamembrane, transmembrane and cytoplasmic tail of ACE2 do not resemble ACE but these two proteins share the CLD region, a 220 amino-acid domain.
T35 9943-10007 Sentence denotes Angiotensin converting enzymes (ACE) are zinc metallopeptidases.
T36 10008-11189 Sentence denotes ACE, is a widely distributed protein of 170 kDa encoded by a 21 kb gene located on chromosome 17 (17q23),45 , 46 that converts the inactive decapeptide, angiotensin (Ang) I to an active vasoconstrictor octapeptide Ang II [Asp-Arg-Val-Tyr-Ile-His-Pro-Phe] that controls the blood pressure,47, 48, 49, 50 and through inactivation of bradykinin vasodilatator.51 AngII also triggers the release of aldosterone that regulates the capacity of kidney to absorb sodium and water.52 Moreover, Ang II stimulates DPP4 activity likely via the seven-transmembrane receptor (7TM) angiotensin II type A receptor (AT1R)-mediated transactivation of epidermal growth factor receptor53 and DPP4 inhibitors are described as a new class of anti-diabetic treatments the cardiovascular safety of which has been confirmed whereas their impact on hypertension is under evaluation.54 Ang II also mediates cell proliferation by stimulating various cytokines.55 ACE2, known for its diverse biological functions, including regulation of blood pressure through the renin-angiotensin-aldosterone system (RAAS), converts the octapeptide AngII to the heptapeptide Ang (1–7) by hydrolysis of the C-terminal residue.
T37 11190-11664 Sentence denotes Ang (1–7) is expect to exert its action through the MAS-related (MAS1) G protein-coupled receptor (GPGR).56 , 57 In the pancreas ACE2 play an important glycemia-protective role.58 Low ACE2 expression in the kidney is also associated with progressive renal diseases including diabetic nephropathy.59 A soluble form of the catalytic ACE2 ectodomain can be released in the circulation following cleavage between amino acids 716 and 741 by sheddase ADAM10 and ADAM17.60, 61, 62.
T38 11665-11788 Sentence denotes The transcriptional regulation of ACE2 is under the control of DNA-binding protein such as Sirtuin 1 (SIRT1).63 (Fig. 1 A).
T39 11789-11800 Sentence denotes Figure 1 A.
T40 11801-11852 Sentence denotes Schematic representation of the regulation of ACE2.
T41 11853-11972 Sentence denotes The transcription of the Ace2 gene is under control of the SIRT1 DNA-binding protein that binds the Ace2 gene promotor.
T42 11973-12059 Sentence denotes Post-transcriptional regulation by miRNA (miRNA143, miRNA421) could occur (not shown).
T43 12060-12273 Sentence denotes Following translation the newly synthesized ACE2 proteins are likely target of post-transcriptional modifications such as phosporylation of Ser680 by AMPK that enhances the stability of ACE2, and N-glycosylations.
T44 12274-12504 Sentence denotes Once expressed at the cell membrane the ACE2 protein can be regulated by sheddases (ADAM10, ADAM17) that cleave the ACE2 extracellular domain and release a circulating soluble form sACE2 capable to interact with integrins (ITGB1).
T45 12505-12507 Sentence denotes B.
T46 12508-12583 Sentence denotes Schematic representation (left) of the ACE2 molecule and its major domains.
T47 12584-12621 Sentence denotes The amino acids position is in black.
T48 12622-12801 Sentence denotes Some of the amino acids important for viral tropism are in red (previous studies showed that residues 31, 41, and regions 82–84 and 353–357 are important for viral spike binding).
T49 12802-12946 Sentence denotes Clustal Omega multiple sequence alignment (EMBL-EBI bioinformatic tool; Copyright © EMBL 2020) of human ACE2 and its different isoforms (right).
T50 12947-13365 Sentence denotes The comparison of the reference Homo sapiens ACE2 protein sequence (S1=Genbank: BAB40370.1) with 9 others ACE2 sequences from the NCBI reference sequence database (S2=UniProtKB Q9BYF1.2; S3=NCBI NP_001358344.1; S4=NCBI NP_068576.1; S5= GenBank EAW98892.1; S6= GenBank AAH48094.2; S7= GenBank AAH39902.1; S8= GenBank AAO25651.1; S9= GenBank BAD99267.1; GenBank AAF99721.1), showed 100% amino acids identity (not shown).
T51 13366-13645 Sentence denotes The Clustal MSA was also used for the comparison of the human ACE2 S1 sequence and available sequences of ACE2 isoforms: the isoform X1 (I1) = NCBI XP_011543851.1; isoform X2 (I2) = NCBI XP_011543853.1; isoform X3(I3) = NCBI XP_011543854.1; isoform CRA (I4) = GenBank EAW98891.1.
T52 13646-13775 Sentence denotes The figure illustrates that these isoforms correspond to deletions in the CLD domain, or truncations in the transmembrane domain.
T53 13776-13900 Sentence denotes A very elegant work by Cao and colleagues42 has recently analyzed 1700 ACE2 variants in search of ACE2 protein polymorphism.
T54 13901-13974 Sentence denotes The mutations and truncations found by this team are shown in light blue.
T55 13976-14006 Sentence denotes ACE2 polymorphism and diseases
T56 14007-14080 Sentence denotes ACE2 limits the adverse vasoconstrictor and profibrotic effects of AngII.
T57 14081-14544 Sentence denotes The hydrolysis of AngII into Ang (1–7) reduces the oxidative stress of AngII on endothelial cerebral arteries.64 Ang (1–7) was reported to have vasodilatory and antifibrotic actions.65 Disruption of ACE2 results in increased AngII levels and impaired cardiac function.66 Reduced levels of cardiac ACE2 have been reported in hypertension (HT) and diabetic heart disease.67 , 68 Low expression of ACE2 mRNA was associated to HT, dyslipidemia and/or heart failure.69
T58 14545-15302 Sentence denotes A polymorphism of ACE2 gene was first documented in the Chinese population with three ACE2 variants (rs4240157, rs4646155, and rs4830542) associated with HT,70, 71, 72, 73, 74 in a Nicotine Dependence in Teens Canadian cohort rs2074192, rs233575, and rs2158083 mutations were significantly associated with pathological variations of blood pressure.75 ACE2 rs21068809 mutation (C > T) has been reported associated with clinical manifestations of HT.76 In Indian the study of 246 HT patients and 274 normotensive people indicated an association of HT with ACE2 rs21068809 mutation.77 In Brazilian patients, the combination of ACE I/D and ACE2 G8790A polymorphisms revels susceptibility to HT.78 The RAAS pathway can also be regulated by a polymorphism in ACE.
T59 15303-15376 Sentence denotes In African-American with hypertension an ACE polymorphism was reported.79
T60 15377-15755 Sentence denotes Very recently, Cao and colleagues reported the results of a large investigation (1700 variants) of coding sequences variants in ACE2 and the allele frequency differences between populations in ACE2 gene from the China Metabolic Analytics Project and 1000 Genome Project database and other large scale genome databases.41 They found one variant with a truncation Gln300 in China.
T61 15756-15855 Sentence denotes In addition, they reported 32 variants among which seven hotspot variants in different populations.
T62 15857-15917 Sentence denotes Viral ACE2 receptor polymorphism and coronaviruses infection
T63 15918-16095 Sentence denotes It remains possible that ACE2 gene polymorphism, human ACE2 mRNA expression and human ACE2 protein polymorphism influence SARS-CoV-2 susceptibility and COVID-19 disease outcome.
T64 16096-16395 Sentence denotes For more than two decades, in the field of the human immunodeficiency virus (HIV), a retrovirus transmitted by sexual intercourse, it was demonstrated that the binding of the gp120 viral envelope glycoprotein to the CD4 receptor,80 , 81 to CXCR482 , 83 or CCR5 coreceptor,84 triggers cell signaling.
T65 16396-16506 Sentence denotes These molecules play a crucial role in the permanent molecular crosstalk between the cell and its environment.
T66 16507-17429 Sentence denotes In this viral model, the study of the CCR5 co-receptor polymorphism clearly showed that a natural Δ32 deletion prevented the infection by HIV of homozygous people carrying this genotype.85 , 86 For the MERS-CoV, attachment of the spike (S) glycoprotein to human cells require the host cell typeII transmembrane protein dipeptidyl peptidase 4 (DPP4/CD26).87 , 88 Following interaction with DPP4, the S protein of MERS-CoV undergoes proteolytic activation through the cellular serine protease TMPRSS2 and cysteine protease cathepsin L once inside endosomes.89 Soluble forms of DPP4 can be released in the blood circulation after cleavage by the kallikrein-related peptidase 5 (KLK5).90 It was recently reported that among fourteen characterized mutants forms of DPP4, four polymorphisms (K267E, K267N, A291P and Δ346-348) strongly reduce the binding and penetration of MERS-CoV into target cells and the viral replication.91
T67 17430-17665 Sentence denotes Regarding SARS-CoV, the S1 domain of the spike protein mediates ACE2 receptor binding whereas the S2 domain is a membrane-associated portion that likely undergoes post-binding transconformational modifications allowing membrane fusion.
T68 17666-18216 Sentence denotes The viral receptor binding domain (RBD) located in S1 has been narrowed down to amino acid residues 318 to 510.92 A co–crystal structure of ACE2 to the RBD revealed that residues 424 to 494 are involved in direct contact with the first α-helix and Lys353 and proximal residues at the N-terminus of β-sheet 5 of ACE2.93 By altering the His353 amino acid in rat ACE2 and modifying a glycosylation site (Asp 90) that may alter the conformation of the α-helix 1 of ACE2, Li and colleagues93 converted the rat ACE2 into an efficient receptor for SARS-CoV.
T69 18217-19046 Sentence denotes A point mutation Leu584Ala in ACE2, markedly attenuated the shedding of the enzyme and facilitated SARS-CoV entry into target cells.61 A soluble form of ACE2 lacking the cytoplasmic and transmembrane domain of the molecule was reported capable of blocking binding of SARS-CoV spike protein to ACE2.94 Expression of ACE2 was found down regulated in cells infected by SARS-CoV.95 A recombinant SARS-CoV spike protein was found to down regulated ACE2 expression through release of sACE2 and thereby promotes lung injury.96 Among other antiviral effect of Chloroquine on SARS-CoV in vitro one could be attributable to a deficit in the glycosylation of the ACE2 virus cell surface receptor.97 , 98 Regarding the HCoV-NL63 that also employ ACE2 for cell entry a recombinant SARS-CoV/HCoV-NL63 spike protein trigger shedding of sACE2.99
T70 19047-19409 Sentence denotes Very recently, investigation of SARS-CoV-2 cell entry through ACE2 binding showed important commonalities between SARS-CoV and SARS-CoV-2 infection, including similar choice of entry receptors.32 SARS-CoV and SARS-CoV-2 share about 76% amino acids identity and most amino acid residues essential for ACE2 binding were conserved in the SARS-CoV-2 spike S1 domain.
T71 19410-19726 Sentence denotes Another recent paper published reported the structural basis of SARS-CoV2 interaction with ACE2.3 The trimeric SARS-CoV-2 S1 spike binds the PD domain of ACE2 and the cleavage of ACE2 C-terminal segment (residues 697 to 716) by the transmembrane protease serine 2 (TMPRSS2) enhances the S-protein-driven viral entry.
T72 19727-20076 Sentence denotes By comparing the 805 amino acid residues of the 10 human ACE2 proteins and the 4 different ACE2 isoforms available through GeneBank using Clustal Omega multiple sequence alignment, a 100% identity among the complete ACE2 sequences was observed and the isoforms corresponded to a deletion in the CLD domain, or truncation in the transmembrane domain.
T73 20077-20170 Sentence denotes The role of these isoforms in SARS-CoV-2 infection and COVID-19 outcome, remains speculative.
T74 20171-20420 Sentence denotes According to the recent work by Cao and colleagues,41 32 variants of ACE2 where characterized among which seven hotspot variants (Lys26Arg, Ile486Val, Ala627Val, Asn638Ser, Ser692Pro, Asn720Asp, and Leu731Ile/Phe) in different populations (Fig. 1B).
T75 20421-20526 Sentence denotes This open the possibility that some people could be less susceptible to SARS-CoV-2 infection than others.
T76 20528-20538 Sentence denotes Discussion
T77 20539-20659 Sentence denotes ACE2 protein at the surface of lung alveolar epithelial cells allows infection of the respiratory tract with SARS-CoV-2.
T78 20660-20758 Sentence denotes It can be hypothesized that the ACE2 levels correlate with susceptibility to SARS-CoV-2 infection.
T79 20759-21078 Sentence denotes Apparently, men have a higher ACE2 expression in lung than women and Asian people express ACE2 higher than Caucasian and African American populations.37 This is in agreement with the finding that conversion of Ang II to Ang (1–7) by ACE2 was higher in males than female,100 suggesting an over-expression of ACE2 in men.
T80 21079-21483 Sentence denotes Because ACE2 is encoded by a gene located on the X chromosome and men express more ACE2 than women it could be speculated that depending the allele expressed by women, they could be considered of lower sensitivity against the most severe adverse effects of the infection.99 , 101 All clinical reports published to date indicate that men represent between 66% and 75% of the most severe cases of COVID-19.
T81 21484-21739 Sentence denotes During early SARS-CoV-2 infection and viral spread within body tissues, the ACE2 function is likely impaired either by steric hindrance of the peptidase domain of ACE2 following virus binding or by down regulation of ACE2 mRNA expression and ACE2 protein.
T82 21740-21895 Sentence denotes In severe COVID-19 disease, the presence of the viral receptor on other tissues than lung may explain the multi-organ failure sometimes observed in clinic.
T83 21896-22011 Sentence denotes We therefore suggest that quantification of ACE2 and AngII be added to the COVID-19 patients biological monitoring.
T84 22012-22098 Sentence denotes It is known that ACE2 can shift the RAAS balance by conversion of Ang II to Ang (1–7).
T85 22099-22426 Sentence denotes Consequently, HT and COVID-19 recently become a question of concern for international professional societies of cardiology regarding: i) the susceptibility of patients with HT to get COVID-19; ii) the severity of the disease; and, iii) the use of ACE inhibitors (ACEi) and AngII receptor blockers (ARBs, that targets the AT1R).
T86 22427-22503 Sentence denotes It is known that HT inhibitors increase the cell-surface expression of ACE2.
T87 22504-22776 Sentence denotes It was demonstrated that ACEi can increase intestinal ACE2 mRNA expression.102 Although data are lacking regarding the effects of such drugs on ACE2 mRNA expression in lung epithelial cells, there is a concern that patients taking those treatments can favor virus capture.
T88 22777-24266 Sentence denotes In patients with HT who received long-term olmesartan (ARB) treatment, urinary ACE2 levels were higher than among untreated control patients.103 In contrast to HT, in patients suffering from idiopathic pulmonary fibrosis, the expression levels of ACE2 are markedly decreased.30 ACE2 is a major actor toward resolution of inflammation and fibrosis.104 In an animal model of bleomycin-induced pulmonary fibrosis, treatment with intraperitoneal injection of recombinant human ACE2 improved the lung function and decreased lung inflammation and fibrosis.105 Moreover, impaired phosphorylation of ACE2 Ser680 by AMP-activated protein kinase in pulmonary endothelium leads to a labile ACE2 and hence pulmonary HT.106 We must also paid attention to molecules such as xanthenone (XNT) and dimiazene aceturate (DIZE, an anti-trypanosomal drug) described as ACE2 activators.107 In a rat model of ischemic heart disease, the subcutaneous infusion of DIZE significantly increased cardiac ACE2 mRNA expression and ACE2 protein catalytic activity, reduced ACE mRNA expression, and improved cardiac remodeling.108 The possible beneficial properties of other molecules such as exenatide (a glucagon-like peptide-1 agonist) which induces an increase in vasodilatory and a decrease in vasoconstrictive mediators must also be investigated.109 In addition, it was recently reported that heparin (anticoagulant) treatment is associated with decreased mortality in severe COVID-19 patients with coagulopathy.110
T89 24267-24817 Sentence denotes In a Chinese cohort of 1099 patients with COVID-19, 165 (13%) individuals were patients with HT, among which 24% suffered from severe COVID-19, a percentage of 3.7%, slightly higher to that of the general population of COVID-19 patients.111 In a smaller cohort of 191 patients with COVID-19, 58 (30%) were patients with hypertension and 48% of them died, which is surprisingly high percentage (14.6%).112 These results suggest that the prevalence of patients with HT was higher in patients who developed severe COVID-19 disease than those who do not.
T90 24818-25157 Sentence denotes By mid march 2020, the international professional societies of cardiology recommended continuing patients' treatment.113 Indeed, when the SARS-CoV-2 spike binds its ACE2 receptor in the α helix 1 (Lys31, Tyr 41) and β5 region (Lys353) it likely reduces the catalytic properties of ACE2 that is usually associated with reduced inflammation.
T91 25158-25419 Sentence denotes The lack of Ang (1–7) generation may increase lung injury114 , 115 and cardiovascular risks, Ang II acting like an inflammatory cytokine.116 In a murine model it was observed that lung inflammation aggravates AngII-induced induced abdominal aortic aneurysms.117
T92 25420-26105 Sentence denotes Mutations might modify the expression level of ACE2 protein as shown in a murine model.118 The deletion of ACE2 in mice model was associated with increased circulation and tissue AngII levels and led to cardiovascular damage.119 , 120 It remain possible that i) mutations affecting the human ACE2 gene; ii) transcriptional variation in ACE2 mRNA expression; iii) post-transcriptional modifications that act on the ACE2 viral receptor (such as N-glycosylation), and; iv) putative ACE2 protein mutations, may influence the outcome of COVID-19 by acting on blood pressure through the RAAS and possible increasing of lung and heart damages through the oxidative stress triggered by Ang II.
T93 26106-26209 Sentence denotes Recently an high rate fatality of SARS-CoV-2 was reported in Iran,121 without satisfactory explanation.
T94 26210-26452 Sentence denotes If underreporting of the number of infected people can be excluded, it could be hypothesized: i) a more aggressive variant clade of SARS-CoV-2122; ii) a variation in ACE2; or, iii) a variation in genes like those encoding Toll-like receptors.
T95 26453-26832 Sentence denotes Since it is known that Ang (1–7) prevents inflammation by inhibiting the resistin/Toll-like receptor 4 (TLR4)/MAPK/NF-kB pathway123 and that there is a high variability of the TLR4 gene in different ethnic groups in Iran,124 it remains possible that SARS-CoV-2 triggers increased inflammation in Iranian patients by suppressing the ACE2-mediated metabolism of AngII to Ang (1–7).
T96 26833-27012 Sentence denotes This could be related to the observation that mice deficient in the TLR3/TLR4 adaptor TRIF are highly susceptible to SARS-CoV infection including severe inflammatory induction.125
T97 27013-27181 Sentence denotes The mechanism of acute myocardial injury caused by SARS-CoV-2 during severe COVD-19 disease might be related to the inhibition of ACE2 catalytic activity.126 (Fig. 2 ).
T98 27182-27418 Sentence denotes Interestingly, a recent study posted as a pre-print paper127 pointed out a list of 97 approved drugs that may have a therapeutic potential against COVID-19 including anti-diabetics (metaformin), statins (simvastatin) and ARBs (sartans).
T99 27419-27584 Sentence denotes Medical records of patients currently treated with these compounds may help to identify whether those drugs have a beneficial or adverse effect on COVID-19 patients.
T100 27585-27859 Sentence denotes Metaformin was also identified as a potential drug-repurposing against SARS-CoV-2 in another study.128 It should be remembered that a large number of data suggest that there is a mild or severe cytokine storm in severe COVID-19 patients which is an important cause of death.
T101 27860-28394 Sentence denotes To reduce the pro-inflammatory effect of AngII and the cytokine storm observed in severe cases of COVID-19, it might make sense to continue treating patients with ACE inhibitors and ARBs, a conclusion shared by recent recommendations of the international societies of cardiology.129 However, Fang and colleagues115 recently reported that the most distinctive comorbidities in patients who died from COVID-19 are HT, coronary heart diseases, cerebrovascular diseases and diabetes, and among them several were treated by ACE inhibitors.
T102 28395-28531 Sentence denotes How should clinicians navigate this uncertainty for patients who are taking ACE inhibitors and ARBs and become infected with SARS-CoV-2?
T103 28532-28724 Sentence denotes Do these molecules have a harmful effect in the outcome of the disease or is the link that is made highlights only a confounding factor which confirms that HT is a major factor of comorbidity?
T104 28725-28915 Sentence denotes In agreement with others,130, 131, 132, 133 we consider that it is of special importance to rapidly evaluate whether these drugs are more beneficial than harmful in severe COVID-19 patients.
T105 28916-29012 Sentence denotes Figure 2 Simplified diagram of the renin-angiotensin system in normal and pathologic conditions.
T106 29013-29106 Sentence denotes The left panel indicates that ACE2 converts Ang II to Ang (1–7) leading to protective signal.
T107 29107-29220 Sentence denotes The right panel illustrates the possible dysfunction of signals when SARS-CoV-2 is attached to its ACE2 receptor.
T108 29221-29429 Sentence denotes Under this condition Ang (1–7) is no longer synthetized, Ang II accumulates and binds AT1R, leading to proinflammatory signals that trigger both tissues damage (in particular lung and heart) and hypertension.
T109 29431-29438 Sentence denotes Funding
T110 29439-29624 Sentence denotes This work was supported by the French Government under the « Investissements d'avenir » (Investments for the Future) program managed by the Agence Nationale de la Recherche (French ANR:
T111 29625-29703 Sentence denotes National Agency for Research), (reference: Méditerranée Infection 10-IAHU-03).
T112 29705-29721 Sentence denotes Ethical approval
T113 29722-29735 Sentence denotes Not required.
T114 29737-29770 Sentence denotes Declaration of Competing Interest
T115 29771-29852 Sentence denotes CD declare a link of interest with the Sanofi and Merck pharmaceutical companies.
T116 29853-29910 Sentence denotes JMR and DR declare that they have no competing interests.