Epistemic_Statements  

CORD-19:02d18b4f484a0420c21595a95b8765125d4a484c JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T1 417-506 Epistemic_statement denotes After the cloning of ACE2 in 2000, three major ACE2 functions have been described so far.
T2 936-1104 Epistemic_statement denotes Third, both ACE2 and its homologue Collectrin can associate with amino acid transporters and play essential role in the absorption of amino acids in the kidney and gut.
T3 1408-1643 Epistemic_statement denotes Abnormal activation of the RAS has been associated with the pathogenesis of cardiovascular and renal diseases such as hypertension, myocardial infarction and heart failure (Ferrario, 1990; Nicholls et al., 1998; Fleming et al., 2006) .
T4 2063-2361 Epistemic_statement denotes Although there exist alternative Ang II-generating enzymes (such as cathepsins and chymase) (Belova, 2000; Miyazaki and Takai, 2006) , it has been thought that ACE is the key and possibly sole enzyme in the regulation of Ang II production in the RAS (Skeggs et al., 1980; Turner and Hooper, 2002) .
T5 2362-2497 Epistemic_statement denotes In 2000, a homologue of ACE, angiotensin-converting enzyme 2 (ACE2), has been discovered (Donoghue et al., 2000; Tipnis et al., 2000) .
T6 2498-2647 Epistemic_statement denotes Accumulated evidences indicate that ACE2 negatively regulates the activated renin-angiotensin system by degrading Ang II to the heptapeptide Ang 1-7.
T7 2648-2855 Epistemic_statement denotes Several studies support a counter-regulatory role for Ang 1-7 by opposing many AT1 receptor-mediated actions, especially in vasoconstriction and cellular proliferation (Santos et al., 2005; Ferrario, 2006) .
T8 2975-3177 Epistemic_statement denotes In addition to its capacity to generate Ang-(1-7), ACE2 is a multifunctional enzyme and its beneficial effects may be a result of its ability to act on other vasoactive peptides (Vickers et al., 2002) .
T9 3466-3683 Epistemic_statement denotes Interestingly, SARS receptor function of ACE2 is independent of its catalytic activities for Ang II degradation, whereas ACE2-mediated Ang II degradation is still important for lung protection from SARS pathogenesis .
T10 3873-3979 Epistemic_statement denotes Collectrin might also have a role in insulin secretion in pancreatic β-cells and/or growth of islet cells.
T11 5192-5260 Epistemic_statement denotes However, the biological significance of soluble ACE remains unclear.
T12 5873-6170 Epistemic_statement denotes 1) , a noncatalytic protein recently shown to have a critical role in amino acid re-absorption in the kidney (Danilczyk et al., 2006; Malakauskas et al., 2007; Verrey et al., 2009) , pancreatic beta cell proliferation (Akpinar et al., 2005) , and possibly insulin exocytosis (Fukui et al., 2005) .
T13 6819-7024 Epistemic_statement denotes ACE2 localization was mapped to the apical surface of epithelial cells, which is in contrast to ACE, which appears to be evenly distributed between the apical and basolateral membranes in polarized cells .
T14 8297-8546 Epistemic_statement denotes Despite the similarities, ACE and ACE2 function differently; ACE releases a C-terminal dipeptide from its substrate (dipeptidylpeptidase), whereas ACE2 cleaves a single amino acid (monocarboxypeptidase) (Donoghue et al., 2000; Tipnis et al., 2000) .
T15 8701-9020 Epistemic_statement denotes While ACE converts Ang I to the potent vasoconstrictor Ang II (Corvol et al., 1995) , ACE2 cleaves Ang I to generate the presumably inactive Ang 1-9 peptide (Donoghue et al., 2000; Tipnis et al., 2000) , which then can be converted to the vasodilator peptide Ang 1-7 by ACE or other peptidases (Donoghue et al., 2000) .
T16 9894-10268 Epistemic_statement denotes Although there were already known Ang 1-7-forming enzymes, such as neprilysin (Yamamoto et al., 1992) , prolyl endopeptidase 24.26 (Nozaki et al., 1992) , and thimet oligopeptidase (Chappell et al., 2000) , the identification of ACE2 has added further support to the biological significance of the Ang 1-7 (Donoghue et al., 2000; Tipnis et al., 2000; Vickers et al., 2002) .
T17 10269-10481 Epistemic_statement denotes This peptide has been shown to interact with the G-protein-coupled receptor Mas to mediate its vasoprotective effects (Santos et al., 2003; Keidar et al., 2007; Raizada and Ferreira, 2007; Alenina et al., 2008) .
T18 10989-11238 Epistemic_statement denotes Interestingly, modification of the C-terminal residue of Apelin-13 (F13A) lost its hypotensive action and further antagonized the effect of wild type Apelin-13 (Lee et al., 2005) , implicating putative roles of ACE2 in metabolism of Apelin peptides.
T19 11441-11595 Epistemic_statement denotes However, the presence of chloride ions increases the hydrolysis of Ang I by ACE2, but inhibits cleavage of the vasoconstrictor Ang II (Guy et al., 2003) .
T20 11596-11782 Epistemic_statement denotes It has been proposed that chloride binding induces subtle changes in the conformation of the active site, which either facilitate or hinder substrate binding (Ehlers and Riordan, 1991) .
T21 11993-12210 Epistemic_statement denotes This would have the effect of increasing the localized concentration of the vasoconstrictor Ang II in the kidney, where both ACE and ACE2 have high levels of expression and extracellular chloride ion levels fluctuate.
T22 13450-13508 Epistemic_statement denotes However, it is not clear how specific these compounds are.
T23 13509-13668 Epistemic_statement denotes Although ACE2 functions as a peptidase to catalyze Ang II cleavage, recent studies demonstrate that transmembrane domain of ACE2 has also biological functions.
T24 13867-14059 Epistemic_statement denotes Cells expressing catalytic inactive mutants of ACE2 are still permissive for SARS-CoV infection, indicating that the peptidase actions of ACE2 are not necessary for SARS entry into host cells.
T25 14555-14649 Epistemic_statement denotes Thus, although detailed mechanisms are still elusive, the transmembrane domain of ACE2 is Fig.
T26 15205-15321 Epistemic_statement denotes It should be noted that ACE2 is an unspecific protease and can cleave multiple additional substrates such as Apelin.
T27 15550-15699 Epistemic_statement denotes Collectrin shares 47.8% identity with C-terminal end of ACE2; however, unlike ACE2, Collectrin lacks active carboxypeptidase catalytic domains ( Fig.
T28 15706-15973 Epistemic_statement denotes The initial report documented that Collectrin localized in the cytoplasm of collecting duct epithelial cells, but further studies indicated the predominant localization of Collectrin in brush borders of the proximal tubular epithelial cells (Danilczyk et al., 2006) .
T29 16247-16551 Epistemic_statement denotes Biochemical studies indicated that Collectrin binds to B 0 AT1 neutral amino acid transporters and plays critical roles for proper expression of these transporters on cell surface required for amino acid re-absorption in proximal tubules of the kidney (Danilczyk et al., 2006; Malakauskas et al., 2007) .
T30 17243-17490 Epistemic_statement denotes Although transcriptional regulation of ACE2 is still elusive, accumulating evidences have indicated that inhibition of RAS by ACE inhibitors or AT1 receptor blockers upregulates ACE2 mRNA expression (Ishiyama et al., 2004; Ferrario et al., 2005) .
T31 17748-17958 Epistemic_statement denotes Inhibition of mineralcorticoids (or aldosterone) increased ACE2 mRNA in macrophages likely through suppression of oxidative stress, which is associated with Ang II and/or NF-κB signaling (Keidar et al., 2005) .
T32 18093-18203 Epistemic_statement denotes Thus, inflammatory signals, including Ang II, cytokines, and NF-κB, are likely to suppress ACE2 transcription.
T33 18338-18576 Epistemic_statement denotes Tissue local hypoxia increases ACE2 expression in human and rat myocardial infarction (Burrell et al., 2005) , although in another model of rat, myocardial infarction changes in ACE2 mRNA levels were not observed (Ishiyama et al., 2004) .
T34 18928-19040 Epistemic_statement denotes Thus, the regulation ACE2 expression under hypoxia is still elusive and may be context or cells/organ-dependent.
T35 19041-19170 Epistemic_statement denotes All-trans retinoic acid has also been shown to elevate ACE2 mRNA levels in spontaneously hypertensive rats (Zhong et al., 2004) .
T36 19806-19928 Epistemic_statement denotes Thus, one can speculate that ACE2 and Collectrin gene expression is coordinately regulated by HNF-1 transcription factors.
T37 19929-20244 Epistemic_statement denotes ACE2 was identified as a SARS receptor (Li et al., 2003) and is has been reported that ACE2 as an intact molecule and/or its transmembrane domain are internalized together with SARS-CoV upon infection, since endocytosis is essential for establishment of the virus entry (Blau and Holmes, 2001; Inoue et al., 2007) .
T38 20245-20284 Epistemic_statement denotes The internalization can take place Fig.
T39 20816-20893 Epistemic_statement denotes Whether such ACE2 cleavage contributes to SARS pathogenesis is not known yet.
T40 21124-21224 Epistemic_statement denotes Whether ACE2 cleavage contributes to supplying neutral amino acids for the B 0 AT1 is not known yet.
T41 21225-21357 Epistemic_statement denotes even when recombinant SARS Spike protein, the SARS-CoV surface ligand for receptor binding, interacts with ACE2 Wang et al., 2008) .
T42 21490-21741 Epistemic_statement denotes However, the role of the cytoplasmic tail of ACE2 is controversial; for instance, deletion of the cytoplasmic tail of ACE2 did not affect SARS-CoV entry (Inoue et al., 2007) , whereas it attenuated SARS-CoV entry in another study (Haga et al., 2008) .
T43 21896-21980 Epistemic_statement denotes The process can be stimulated by phorbol ester, ionomycin, endotoxin, IL-1β or TNFα.
T44 22427-22771 Epistemic_statement denotes Although the physiological role of ACE2 ectodomain shedding remains elusive as roles for circulating ACE2 and remnant Cterminal domain have yet to be identified, shedding seems to be involved in SARS-CoV cellular entry and replication and an ADAM17 inhibitor suppresses SARS-CoV replication in vitro (Glowacka et al., 2010; Haga et al., 2008) .
T45 23331-23581 Epistemic_statement denotes In humans, several studies have shown a strong association of ACE2 polymorphisms to hypertension in female Chinese patients with metabolic syndrome (Zhong et al., 2006) or essential hypertension (Yi et al., 2006; Fan et al., 2007; Niu et al., 2007) .
T46 23724-23888 Epistemic_statement denotes However, genetic inactivation of ACE2 using homologous recombination results in no apparent alterations in blood pressure in basal levels (Crackower et al., 2002) .
T47 23997-24252 Epistemic_statement denotes This is a sharp contrast to spontaneous hypotension observed in ACE knockout mice (Krege et al., 1995) , suggesting that, in addition to the Ang II system, ACE2 might regulate blood pressure through other peptide systems, such as bradykinin and/or Apelin.
T48 24547-24760 Epistemic_statement denotes In addition to hypertension, ACE2 gene delivery has also shown beneficial effects on atherosclerosis in animal models, suggesting that ACE2 confers endothelial protection (Dong et al., 2008; Lovren et al., 2008) .
T49 24887-25126 Epistemic_statement denotes ACE2 null mice displayed impaired cardiac contractility which is associated with aging and/or cardiac pressure overload in several different ACE2 knockout mouse lines (Crackower et al., 2002; Yamamoto et al., 2006; Nakamura et al., 2008) .
T50 25127-25433 Epistemic_statement denotes Heart contractility impairment was correlated with elevated cardiac and plasma Ang II levels, and double knockout mice of ACE and ACE2 genes or treatment with AT1 receptor blockers reversed the cardiac phenotype in ACE2 knockout mice (Crackower et al., 2002; Yamamoto et al., 2006; Nakamura et al., 2008) .
T51 25560-25782 Epistemic_statement denotes Mechanistically, the agedependent cardiomyopathy in ACE2 knockout mice is likely mediated by Ang II-induced oxidative stress and inflammation through AT1 receptor downstream PI3K (phosphatidylinositol-3-kinase) signaling .
T52 25783-26008 Epistemic_statement denotes Of note, one study reported that their knockout mouse line did not show alterations in cardiac function, although these mice were not investigated under conditions of cardiac like pressure overload Gurley and Coffman, 2008) .
T53 26009-26126 Epistemic_statement denotes However, these differences were resolved and appear to be dependent on modifier genes in different mouse background .
T54 26520-26815 Epistemic_statement denotes Treatment with Ang 1-7 peptide has been shown to improve myocardial performance, cardiac remodeling, and even survival in rodent heart failure models, including ischemia/reperfusion injury, myocardial infarction, hypertension-induced cardiomyopathy (Ferreira et al., 2001; Santos et al., 2004) .
T55 27050-27203 Epistemic_statement denotes Although there are accumulating literatures on ACE2-Ang 1-7-Mas axis, most of them are correlative studies on ACE2 relationships with Ang 1-7-Mas system.
T56 27204-27310 Epistemic_statement denotes We still miss direct evidence linking functional causal relationships between ACE2 and Ang 1-7-Mas system.
T57 27311-27435 Epistemic_statement denotes For instance, whether Ang 1-7 peptide or Mas agonist can rescue ACE2 knockout mouse heart phenotypes is not even challenged.
T58 28092-28332 Epistemic_statement denotes Interestingly, Apelin knockout mice showed aging-or stress-associated cardiac contractility defects, similar to the heart phenotype of ACE2 knockout mice, implicating a potential in vivo interaction of ACE2 with Apelin (Kuba et al., 2007) .
T59 28333-28458 Epistemic_statement denotes Nevertheless, there are no direct evidences of in vivo catalysis of Apelin peptides by ACE2, and further studies are awaited.
T60 28459-28774 Epistemic_statement denotes In humans, ACE2 gene polymorphisms associate with parameters of left ventricular hypertrophy in men (Lieb et al., 2006) , and soluble ACE2 activity is increased in patients with myocardial dysfunction and correlates with disease severity (Epelman et al., 2008) , implicating physiological roles of ACE2 in patients.
T61 28775-29200 Epistemic_statement denotes For therapeutic applications of ACE2 using transgenic overexpression of ACE2 in the hearts, the phenotypes are controversial; one study showed that cardiac overexpression of ACE2 protects the heart from ischemia-induced heart failure (Der Sarkissian et al., 2008) , whereas in the others overexpression of ACE2 was not beneficial, leading to fatal arrhythmia and severe fibrosis (Donoghue et al., 2003; Masson et al., 2009) .
T62 29201-29486 Epistemic_statement denotes The latter harmful effects may be due to the artifacts of transgenic gene overexpression, since utilizing recombinant ACE2 protein for therapeutic models has been recently shown to be beneficial in various disease models (Oudit et al., 2010; Treml et al., 2010; Wysocki et al., 2010) .
T63 29568-29825 Epistemic_statement denotes Injections of the ACE2 inhibitor MLN4760 into the nucleus tractus solitarii reduced the baroreceptor reflex for reflex bradycardia in rats (Diz et al., 2008; Xia and Lazartigues, 2008) , suggesting a role for ACE2 and RAS in controlling baroreceptor reflex.
T64 30606-30739 Epistemic_statement denotes These phenotypes are at least in part dependent on Ang II signaling and can be rescued by AT1 receptor blockade Soler et al., 2007) .
T65 30740-30821 Epistemic_statement denotes Thus, these data definitely indicate that ACE2 is physiologically renoprotective.
T66 30969-31085 Epistemic_statement denotes Diabetic nephropathy in experimental models has been shown to alter both glomerular and tubular expressions of ACE2.
T67 31516-31685 Epistemic_statement denotes Thus, reduced ACE2 expression might contribute to the pathogenesis and progression of kidney diseases (Tikellis et al., 2003; Mizuiri et al., 2008; Reich et al., 2008) .
T68 31686-31813 Epistemic_statement denotes Renal expression of ACE2 may play a more profound role in controlling local RAS rather than regulating systemic blood pressure.
T69 32237-32430 Epistemic_statement denotes ARDS can be triggered by multiple diseases such as sepsis, aspiration, trauma, acute pancreatitis, or pneumonias following infections with SARS coronavirus or avian and human influenza viruses.
T70 32431-32726 Epistemic_statement denotes Previous studies of ACE insertion/deletion (I/D) polymorphism correlation with severity of ARDS in humans (Marshall et al., 2002; Jerng et al., 2006) and ACE inhibitor treatments in rodent ARDS models (Raiden et al., 2002) have suggested that the RAS could have a role in ARDS/acute lung injury.
T71 33798-34056 Epistemic_statement denotes Moreover, in other lung injury models like bleomycin-induced lung fibrosis and monocrotaline-induced pulmonary hypertension, ACE2 has recently been shown to protect from chronic lung injuries, fibrosis, and pulmonary vasoconstriction Yamazato et al., 2009) .
T72 34057-34321 Epistemic_statement denotes These results suggest that ACE2 may serve as an entirely novel therapeutic for chronic lung diseases as well as acute lung injury, and the efficacy of recombinant ACE2 protein or AT1 receptor blockers on lung diseases should be further tested in clinical settings.
T73 34322-34461 Epistemic_statement denotes During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world.
T74 34649-34937 Epistemic_statement denotes Surprisingly, ACE2 was identified as a functional receptor in vitro by using co-immunoprecipitation techniques (Li et al., 2003) , and subsequently, in a mouse SARS infection model with ace2 knockout mice, ACE2 was indeed identified as the essential receptor for SARS infections in vivo .
T75 35291-35574 Epistemic_statement denotes However, this process does not require nor affect the peptidase activity of ACE2, since cells expressing enzymatically inactive ACE2 can still be infected with the SARS-CoV and ACE2 substrates are still accessible to the catalytic pocket of ACE2 when the SARS Spike protein is bound.
T76 35817-35958 Epistemic_statement denotes One mystery of SARS-CoV is why, in contrast to the other coronaviruses, such infections trigger severe lung disease with such high mortality.
T77 35959-36189 Epistemic_statement denotes Accumulating evidence indicates that severe SARS infections are dependent on the burden of viral replication as well as on the immunopathologic consequences of the host response (Lau and Peiris, 2005; Perlman and Dandekar, 2005) .
T78 37113-37381 Epistemic_statement denotes Although many studies demonstrated that SARS receptor ACE2-expressing cells are alveolar type-1 or type-2 pneumocytes or vascular endothelial cells, a couple of recent studies suggested that lung epithelial stem/ progenitor cells are also important for SARS infection.
T79 37679-37903 Epistemic_statement denotes Detailed expression analyses for mouse lungs revealed the highest expression of ACE2 in late embryonic days (E18.5) which declines after birth (Wiener et al., 2007) and further supporting a role for ACE2 in progenitor cells.
T80 37904-38114 Epistemic_statement denotes In SARS-infected human patient lungs, CD34+ Oct4+ lung progenitor cells are also positive for SARS-CoV antigens using immunohistochemistry, while mature pneumocytes appear to be negative for SARS-CoV antigens .
T81 38115-38280 Epistemic_statement denotes Interestingly, in rabbit atherosclerosis models, co-localization of ACE2 in CD34+ Oct4+ cells was also observed in the atherosclerotic plaques (Zulli et al., 2006) .
T82 38281-38593 Epistemic_statement denotes However, it should be noted that ACE2 expression is downregulated by SARS infection at the transcriptional and posttranslational level (Glowacka et al., 2010; Inoue et al., 2007; Haga et al., 2008; Wang et al., 2008) , and therefore one would actually expect low ACE2-immunoreactivity in SARS-CoV infected cells.
T83 38594-38856 Epistemic_statement denotes Nevertheless, these observations suggest a potential role of ACE2 for lung stem/ progenitor cells, in addition to type-1/type-2 pneumocytes, in the continued destruction of lung tissues and apparent loss in the capacity for lung repair after SARS-CoV infections.
T84 38857-38896 Epistemic_statement denotes Further studies are, however, required.
T85 39583-39762 Epistemic_statement denotes Surprisingly, using gene-targeting studies of Collectrin, the physiological in vivo function of Collectrin turned out to be a critical binding partner for amino acid transporters.
T86 40419-40594 Epistemic_statement denotes However, this was not the case; rather ACE2 binds to the B 0 AT1 amino acid transporter in the intestine but not in the kidney (Kowalczuk et al., 2008; Camargo et al., 2009) .
T87 40595-40780 Epistemic_statement denotes In ACE2 knockout mice, luminal expression of B 0 AT1 in the intestine is completely lost, suggesting that ACE2 is essential for expression of B 0 AT1 in cell surface of the intestine ).
T88 40781-41027 Epistemic_statement denotes Thus, ACE2 and Collectrin are both binding partners for B 0 AT1 and contribute to absorption of neutral amino acids in intestine and kidney, respectively, although reasons for tissue-specific bindings of B 0 AT1 to ACE2 or Collectrin are unknown.
T89 41382-41557 Epistemic_statement denotes Despite crucial roles of ACE2 and Collectrin in expression of this amino acid transporter, gene mutations of ACE2 and Collectrin have not been identified in Hartnup's disease.
T90 41731-41941 Epistemic_statement denotes In in vitro Xenopus oocyte expression system the B 0 AT1 mutants alone show similar levels of amino acid uptake to wild-type one, although the transport rates are low (Seow et al., 2004; Camargo et al., 2009) .
T91 41942-42145 Epistemic_statement denotes However, when the mutants were co-expressed with ACE2, transport function was not activated by the binding partners, while the coexpression of ACE2 and B 0 AT1 dramatically activates transport functions.
T92 42146-42293 Epistemic_statement denotes Thus, mutations in Hartnup disorder patients interfering with the interaction between B 0 AT1 and ACE2 may explain the disease in some individuals.
T93 42596-42772 Epistemic_statement denotes Therefore, the physiological significance of this impaired activation of the mutants by ACE2 is yet elusive, and further analyses for the role of the mutations would be needed.
T94 43014-43235 Epistemic_statement denotes The carboxypeptidase activity of ACE2 appears to limit the availability of Ang II, generates counter-regulatory vasodilator peptides such as Ang 1-7, and may even act on other peptide systems such as Apelin and dynorphin.
T95 43348-43597 Epistemic_statement denotes These findings are now providing the opportunity to develop a potential novel medicine for the treatment of ARDS, an often lethal condition that can develop in emerging infectious lung diseases such as avian influenza (H5N1) or the swine flu (H1N1).
T96 43598-43800 Epistemic_statement denotes During the course of studying ACE2 function, we also made an entirely unexpected finding: ACE2 and Collectrin are essential for expression of amino acid transporters in the gut and kidney, respectively.
T97 43801-44013 Epistemic_statement denotes The discovery and functional characterization of ACE2 have shown that the RAS system is far more complex and that this system is tightly connected to other peptide systems and even amino acid transport functions.
T98 44014-44267 Epistemic_statement denotes An understanding of such complexity and molecular crosstalks will not only broaden our knowledge on the evolution and biology of cardiovascular systems, but will also offer a chance to develop new and refined therapeutic strategies for various diseases.