LitCovid-sample-sentences  

PMC:7556165 / 7723-33370 JSONTXT 18 Projects

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Id Subject Object Predicate Lexical cue
T52 0-5 Sentence denotes ACE2:
T53 6-62 Sentence denotes Structure, Expression, Tissue Distribution, and Function
T54 64-81 Sentence denotes Structure of ACE2
T55 82-203 Sentence denotes ACE2 is a 40 kb gene and it is positioned on chromosome Xp22, differently from ACE gene that is located on chromosome 17.
T56 204-261 Sentence denotes The 18 exons of ACE2 are remarkably similar to ACE exons.
T57 262-551 Sentence denotes The ACE2 gene depicts a large polymorphism and several novel polymorphisms of ACE2, with specific geographical distribution, have been described and associated with susceptibility to hypertension and cardiovascular disease (Burrell et al., 2013; Patel et al., 2014; Pinheiro et al., 2019).
T58 552-672 Sentence denotes The ACE2 gene codifies for a typical zinc-metallopeptidase of 805 amino acids (120 kDa), with a unique catalytic domain.
T59 673-783 Sentence denotes Despite the high resemblance of ACE and ACE2, considerable differences exist in their substrates and products.
T60 784-873 Sentence denotes While ACE acts as dipeptidase, ACE2 removes only a single amino acid from its substrates.
T61 874-1125 Sentence denotes Therefore, ACE2 is not active in transforming angiotensin I to angiotensin II and in inactivating bradykinin; moreover, ACE2 is insensitive to ACE inhibitors, like lisinopril and captopril (Tipnis et al., 2000; Rice et al., 2004; Turner et al., 2004).
T62 1126-1223 Sentence denotes These differences depend on variances in the three-dimensional structure (3D) of the two enzymes.
T63 1224-1332 Sentence denotes Comparative homology modeling and crystallography contributed to shed light on ACE2 3D structure (Figure 1).
T64 1333-1485 Sentence denotes Prabakaran et al. (2004) clarified the major characteristic of ACE2, which is a deep channel on the summit of the protein, hosting the catalytic domain.
T65 1486-1634 Sentence denotes Specific loops, like the long loop N210-Q221 that is exclusive of ACE2, α helices and a portion of β-sheet are located around the catalytic channel.
T66 1635-1795 Sentence denotes The negative charge of the channel and the presence of distinct hydrophobic regions contribute to the specificity of the binding site (Prabakaran et al., 2004).
T67 1796-2058 Sentence denotes The determination of the crystal structure of the extracellular domain to 2.2-3-A resolution from Towler et al. (2004) and the model from Guy et al. (2003) showed that the catalytic domain of ACE and ACE2 are very conserved and have similar mechanisms of action.
T68 2059-2330 Sentence denotes The main difference stems from the smaller ACE2 pocket, thereby lodging only a single amino acid: the crucial substitution of the Gln281 in ACE binding pocket with Arg273 in ACE2 is likely to be responsible for the steric conflict (Guy et al., 2003; Towler et al., 2004).
T69 2331-2567 Sentence denotes Another surprise of the ACE2 structure was its C-terminal domain, which—differently from ACE—revealed high homology with collectrin, a renal protein, which is involved in amino acids trafficking through the membrane (Yang et al., 2017).
T70 2568-2604 Sentence denotes FIGURE 1 Crystal structure of ACE2.
T71 2605-2720 Sentence denotes The peptidase domain (PD) is in green, whereas the collectrin homology domain is enclosed in the light cyan square.
T72 2721-2866 Sentence denotes The active zinc ion is showed enclosed in a red circle, whereas the glycosylation moieties are showed as cyan cubes and denoted by dashed arrows.
T73 2867-2960 Sentence denotes The structures have been drawn from PDB 1R42 (Towler et al., 2004) by Mol on the PDB website.
T74 2962-3042 Sentence denotes Transcriptional, Post-transcriptional, and Post-translational Regulation of ACE2
T75 3043-3326 Sentence denotes The location of the ACE2 gene on the X chromosome questions whether one of the two ACE2 is silenced in females, to balance female/male expression dosage (X chromosome inactivation or XCI), or otherwise belongs to the class of “escape genes” which are transcribed on both chromosomes.
T76 3327-3515 Sentence denotes Interestingly, a wide survey of XCI in several individuals and tissues showed that ACE2 is a heterogeneous escape gene, because it has a tissue-dependent sex bias (Tukiainen et al., 2017).
T77 3516-3668 Sentence denotes A growing number of recent findings point to an important role of epigenetic mechanisms associated with several human diseases (Surguchov et al., 2017).
T78 3669-3843 Sentence denotes In this context, several authors highlighted the regulatory role of 17β-estradiol (E2), a primary female sex steroid, in the expression of ACE2 in a tissue-dependent fashion.
T79 3844-3992 Sentence denotes Liu et al. (2010) and Stelzig et al. (2020) found out that E2 downregulates ACE2 in kidney and differentiated airway epithelial cells, respectively.
T80 3993-4275 Sentence denotes The latter result is particularly important, as the male-bias of ACE2 expression in the lung could account for the alleged higher susceptibility of males to COVID-19 symptoms following ACE2-dependent SARS-CoV-2 infection (section Links Between ACE2 and COVID-19) (Jin et al., 2020).
T81 4276-4448 Sentence denotes Yet, Bukowska et al. (2017) observed that E2 increases ACE2 transcription and expression in human atrial tissue, while at the same time depressing the level of ACE protein.
T82 4449-4660 Sentence denotes This mechanism attenuates the renin-angiotensin system and, in tandem with anti-inflammatory and anti-oxidative effects, enables a stronger response to myocardial stress and contributes to antiarhythmic effects.
T83 4661-4807 Sentence denotes The upregulation of ACE2 (and downregulation of ACE) was clearly linked to binding of E2 to Estrogen Receptor alpha (ERα) (Bukowska et al., 2017).
T84 4808-5048 Sentence denotes The E2-ERα complex might migrate to the nucleus to bind to estrogen response elements, although the actual mechanism is still obscure and should likely involve other co-factors to take into account the observed tissue bias of E2 regulation.
T85 5049-5298 Sentence denotes Nonetheless, it was demonstrated that the Estrogen Related Receptor alpha (ERRα), which likewise ERα recognizes the estrogen response element in target genes, binds to ACE2 promoter to repress transcription (Tremblay et al., 2010; Lee et al., 2012).
T86 5299-5401 Sentence denotes Hopefully, future studies will shed more light on the intriguing role of estrogens in ACE2 regulation.
T87 5402-5564 Sentence denotes A recent analysis of public genomic and transcriptomic data outlined the role of histone methylation, a classical epigenetic mark, to regulate ACE2 transcription.
T88 5565-5726 Sentence denotes Indeed, Li Y. et al. (2020) showed that transcription of ACE2 was significantly upregulated when the histone mutant H3K27M was overexpressed to inhibit H3K27me3.
T89 5727-5809 Sentence denotes Conversely, overexpression of mutant H3K4/9/36M did not change ACE2 transcription.
T90 5810-5965 Sentence denotes Trimethylation of K27 on H3 is catalyzed by the polycomb groups (PcG), a group of conserved transcriptional gene repressors (Schuettengruber et al., 2017).
T91 5966-6028 Sentence denotes PcG proteins assemble into two major complexes: PRC1 and PRC2.
T92 6029-6153 Sentence denotes The simplest model of PcG activity involves trimethylation of H3 by PRC2 at target gene promoters (Blackledge et al., 2015).
T93 6154-6402 Sentence denotes These epigenetic marks recruit PRC1 on DNA, which in turn acts as E3-ligase and ubiquitinates nearby H2A histones (Storti et al., 2019), triggering silencing of gene transcription by local and reversible compaction of chromatin (Illingworth, 2019).
T94 6403-6468 Sentence denotes The catalytic subunit of PRC2 is constituted by the EZH2 protein.
T95 6469-6636 Sentence denotes In agreement with the inverse correlation between ACE2 level and H3K27me3, ACE2 expression in human ESCs was upregulated following EZH2 knock-out (Li Y. et al., 2020).
T96 6637-6700 Sentence denotes On the other side, recovery of EZH2 restored basal ACE2 levels.
T97 6701-6894 Sentence denotes Chromatin immunoprecipitation sequencing (ChIP-seq) showed that EZH2 depletion induced H3K27me3 decrease, with concomitant H3K27ac increase, at ACE2 promoter in human ESCs (Li Y. et al., 2020).
T98 6895-7181 Sentence denotes The role of H3 methylation and acetylation in the epigenetic regulation of ACE2 was also hypothesized by Pinto et al., who demonstrated that co-morbidities such as hypertension, diabetes, and chronic obstructive lung disease increase ACE2 transcription in the lung (Pinto et al., 2020).
T99 7182-7263 Sentence denotes Histone methylation does not appear to exhaust the epigenetic regulation of ACE2.
T100 7264-7412 Sentence denotes Notably, the NAD+-dependent deacetylase SIRT1 binds to ACE2 promoter favoring its transcription during cellular energy stress (Clarke et al., 2014).
T101 7413-7493 Sentence denotes Two recent unrefereed preprints highlighted other epigenetic mechanisms at play.
T102 7494-7698 Sentence denotes Corley et al.1 pointed out that DNA methylation across three CpG islands in the ACE2 promoter was lower in lung epithelial cells compared to other cell types, suggesting high transcription in lung tissue.
T103 7699-7901 Sentence denotes These findings are in excellent agreement with the reported inverse correlation between ACE2 transcription and promoter methylation in tumors, which will be discussed in section ACE2 and Other Diseases.
T104 7902-8084 Sentence denotes This correlation is also supported by the observation that in children ACE2 is normally hypermethylated and poorly expressed either in the lung and in other organs (Pruimboom, 2020).
T105 8085-8306 Sentence denotes Glinsky (2020) addressed the epigenetic role of Vitamin D on ACE2 expression, showing by gene set enrichment analysis that the Vitamin D receptor (VDR) should be involved in a set of regulatory pathways conveying on ACE2.
T106 8307-8516 Sentence denotes More specifically, VDR activation would downregulate ACE2, thus affording a potential reason for the alleged beneficial role of Vitamin D in COVID-19 (section ACE2 and the Inflammatory Response to Sars-CoV-2).
T107 8517-8636 Sentence denotes Finally, the strict homeostatic balance of ACE/ACE2 activities suggests transcriptional co-regulation of both proteins.
T108 8637-8932 Sentence denotes Remarkably, Yang et al. (2016) have demonstrated that a subtle regulatory mechanism acts in cardiac endothelial cells, where the Brg1 chromatin remodeler and the FoxM1 transcription factor cooperate to determine the ACE2/ACE expression ratio, particularly under cardiac hypertrophy of the heart.
T109 8933-8977 Sentence denotes Further regulation occurs at the mRNA level.
T110 8978-9103 Sentence denotes From putative microRNA-binding sites identified in vitro, Lambert et al. (2014) demonstrated that miR-421 downregulates ACE2.
T111 9104-9251 Sentence denotes According to the hypothesized mechanism, miR-421 modulates ACE2 expression by hampering translation rather than by degradation of mRNA transcripts.
T112 9252-9467 Sentence denotes Beside undergoing post-translational modifications by glycosylation and phosphorylation, ACE2 is also post-translationally regulated by shedding from cell membrane through the action of the metalloproteinase ADAM17.
T113 9468-9638 Sentence denotes The proteolysis of ACE2 releases a soluble, enzymatically active form which corresponds to the ACE2 ectodomain (Jia et al., 2009; Xiao et al., 2014; Conrad et al., 2016).
T114 9639-9756 Sentence denotes The function, if any, of soluble ACE2 is still obscure, but the shedding mechanism is under strict molecular control.
T115 9757-9919 Sentence denotes Lambert et al. (2008) highlighted that calmodulin associates with ACE2 to prevent its shedding, while calmodulin inhibitors increase the cellular release of ACE2.
T116 9920-9969 Sentence denotes Patel identified a positive feedback in the RAAS:
T117 9970-10080 Sentence denotes Ang II activates ADAM17, thereby increasing the release of ACE2, its negative regulator (Patel et al., 2016b).
T118 10081-10212 Sentence denotes It is worth noting that high levels of plasma-soluble ACE2 have been associated with myocardial dysfunction (Epelman et al., 2009).
T119 10213-10344 Sentence denotes The potential pathophysiological role of ADAM17 is further discussed in paragraph ACE2 and the Inflammatory Response to Sars-CoV-2.
T120 10345-10465 Sentence denotes Figure 2 summarizes the known transcriptional, post-transcriptional, and post translational regulation pathways of ACE2.
T121 10466-10567 Sentence denotes FIGURE 2 Regulation pathways of transcription, translation, and post-translational shedding of ACE2.
T122 10568-10600 Sentence denotes Red text: non-molecular factors.
T123 10601-10631 Sentence denotes Black text: molecular factors.
T124 10633-10660 Sentence denotes Tissue Distribution of ACE2
T125 10661-10801 Sentence denotes Detectable quantities of ACE2 protein have been found almost ubiquitously in tissues across mammalian species, using immunostaining methods.
T126 10802-11019 Sentence denotes ACE2 is predominantly located in the cardiovascular system and kidney, where it probably plays a role in the maintenance of hydro electrolyte homeostasis (section “Mechanism of Viral Entry Mediated by the S Protein”).
T127 11020-11238 Sentence denotes In fact, ACE2 is pervasively expressed throughout the vasculature, at the level of the arteries and veins, mainly in smooth muscle cells of the media and in the endothelium (Hamming et al., 2004; Burrell et al., 2005).
T128 11239-11329 Sentence denotes Such signal from vessels also delivers part of the expression detected in specific organs.
T129 11330-11668 Sentence denotes Indeed, ACE2 is evident in: coronary vessels and myocardial capillaries (Wiener et al., 2007; Garabelli et al., 2008); lung microvascular endothelial cells (Wiener et al., 2007; Chen et al., 2013); kidney interlobular arteries (Lely et al., 2004); endothelial and smooth muscle cells in the brain (Hamming et al., 2004; Kar et al., 2010).
T130 11669-11846 Sentence denotes Notably, the mesangium and glomerular endothelium in the kidney, and the endothelial lining of the sinusoids in the liver are allegedly negative for ACE2 (Hamming et al., 2004).
T131 11847-12034 Sentence denotes On the contrary, ACE2 is virtually absent from the lymphatic system, and human hemato-lymphoid organs (i.e., spleen, lymph nodes, and bone marrow) (Hamming et al., 2004; Li et al., 2007).
T132 12035-12182 Sentence denotes In blood cells, it has been observed in platelets and macrophages, but not in B and T lymphocytes (Hamming et al., 2004; Fraga-Silva et al., 2011).
T133 12183-12526 Sentence denotes Expression of ACE2 was originally identified in rodent heart (Donoghue et al., 2000a), where it was observed to occur in both atrium an ventricle (Gembardt et al., 2005), and, cellularly, in cardiomyocytes and in specialized cells of the sinoatrial node (Burrell et al., 2005; Garabelli et al., 2008; Ferreira et al., 2011; Wang et al., 2017).
T134 12527-12719 Sentence denotes In human heart, ACE2 has been found in the stromal area in spongiosa layer in aortic valves (Peltonen et al., 2011), where it is expressed in myofibroblasts and fibroblasts (Guy et al., 2008).
T135 12720-13007 Sentence denotes High levels of ACE2 protein expression have been detected in mammalian, including human, kidney (Gembardt et al., 2005; Koka et al., 2008; Reich et al., 2008; Giani et al., 2012; Mitani et al., 2014; Grobe et al., 2015; Shi et al., 2015; Larouche-Lebel et al., 2019; Alawi et al., 2020).
T136 13008-13346 Sentence denotes Strong signals were reported in the brush border of the proximal tubular cells, whereas weak to moderate signals could be found in the glomeruli, Henle’s loop, distal tubules, and collecting duct (Hamming et al., 2004; Lely et al., 2004; Kamilic et al., 2010; Giani et al., 2012; Bae et al., 2015; Cao et al., 2017; Errarte et al., 2017).
T137 13347-13541 Sentence denotes In the respiratory tract of primates, positive labeling for ACE2 has been reported at multiple sites, from the nasal and oral mucosa, to the larynx, trachea, bronchi and lung (Liu et al., 2011).
T138 13542-13827 Sentence denotes Whether ACE2 is expressed in human nasal and oral epithelium remains unclear, as contradictory results have been reported by studies using immunohistochemistry (Hamming et al., 2004; Bertram et al., 2012), in face of positive single-cell RNA sequencing findings (Sungnak et al., 2020).
T139 13828-13998 Sentence denotes This point is of great interest to understand the role of those tissues in SARS-CoV-2 initial infection, spread and clearance (section “Links Between ACE2 and COVID-19”).
T140 13999-14156 Sentence denotes In the upper respiratory tract ACE2 is expressed in the epithelial lining and lamina propria, in some muscle cells and in the salivary gland duct epithelium.
T141 14157-14451 Sentence denotes In the lung, an intense signal for ACE2 protein has been consistently observed in type I and II pneumocytes in several species, including mouse, rat, cat, ferret, monkey and human (Wiener et al., 2007; van den Brand et al., 2008; Liu et al., 2011; Wong et al., 2012; Chen et al., 2013; Zhang B.
T142 14452-14469 Sentence denotes N. et al., 2019).
T143 14470-14634 Sentence denotes Data from rodents suggest an age- and gender-dependent pattern of expression, with a more rapid decline with age in males as compared to females (Xie et al., 2006).
T144 14635-14913 Sentence denotes Although some ACE2 signal has been observed in the liver, it appears to mainly come from small vessel endothelium, and occasionally bile duct epithelial cells, while negligible expression is observed in hepatocytes (Hamming et al., 2004; Paizis et al., 2005; Guan et al., 2020).
T145 14914-15103 Sentence denotes ACE2 protein is abundantly expressed in the brush border of enterocytes of all parts of the small intestine, including the duodenum, jejunum, and ileum, but not in enterocytes of the colon.
T146 15104-15313 Sentence denotes Other organs of the digestive tract, such as the stomach and colon, did not show brush border staining, but rather a positive signal in the muscolaris mucosae and the muscolaris propria (Hamming et al., 2004).
T147 15314-15480 Sentence denotes In rodents, ACE2 is also expressed in both exocrine and endocrine pancreatic tissue, particularly in the islets of Langerhans (Niu et al., 2008; Fang and Yang, 2010).
T148 15481-15571 Sentence denotes ACE2 distribution is widespread in the mouse brain, from the telencephalon to the medulla.
T149 15572-15978 Sentence denotes As expected, ACE2 is found in brain areas involved in the regulation of cardiovascular function and fluid balance, such as the vascular organ of lamina terminalis, subfornical organ, magnocellular neurons in the hypothalamic paraventricular nucleus, area postrema, nucleus of the solitary tract, dorsal motor nucleus of the vagus, nucleus ambiguous, and rostral ventrolateral medulla (Doobay et al., 2007).
T150 15979-16262 Sentence denotes However, significant expression had also been reported in brain areas not engaged in the classical functions of the RAAS, namely the piriform cortex, hippocampus, caudate putamen, hypoglossal nucleus and primary motor cortex (Doobay et al., 2007; Lin et al., 2008; Liu et al., 2014).
T151 16263-16400 Sentence denotes ACE2 immunostaining was identified in neurons as well as astrocytes (Gallagher et al., 2006; Doobay et al., 2007; Yamazato et al., 2007).
T152 16401-16571 Sentence denotes Furthermore, ACE2 has been documented in the retina, predominantly in the inner nuclear layer but also in photoreceptors (Tikellis et al., 2004; Senanayake et al., 2007).
T153 16572-16680 Sentence denotes With regard to the endocrine system, ACE2 expression was found in both male and female reproductive systems.
T154 16681-16818 Sentence denotes In human testis, ACE2 was localized to the Leydig and Sertoli cells, and might be involved in testicular function (Douglas et al., 2004).
T155 16819-17086 Sentence denotes At present, no data about ACE2 protein expression is human ovaries is available, although evidence of expression in stroma, theca, and granulosa cells has been reported in other species (Tonellotto dos Santos et al., 2012; Barreta et al., 2015; Pereira et al., 2015).
T156 17087-17200 Sentence denotes In rodent bone, ACE2 is expressed in osteoblasts and osteoclasts, as well as in epithelial cells and fibroblasts.
T157 17201-17305 Sentence denotes However, a similar expression in human samples still awaits clarification (Queiroz-Junior et al., 2019).
T158 17306-17431 Sentence denotes In human skin, ACE2 was present in the basal cell layer of the epidermis extending to the basal cell layer of hair follicles.
T159 17432-17513 Sentence denotes Smooth muscle cells surrounding the sebaceous glands were also positive for ACE2.
T160 17514-17578 Sentence denotes Weak cytoplasmic staining was observed in sebaceous gland cells.
T161 17579-17663 Sentence denotes A strong granular staining pattern for ACE2 was seen in cells of the eccrine glands.
T162 17664-17844 Sentence denotes Positive staining for ACE2 was also noted in the membrane of human fat cells in various organs, including the epicardial adipose tissue (Hamming et al., 2004; Patel et al., 2016a).
T163 17845-17955 Sentence denotes Globally, ACE2 is chiefly bound to cell membranes, while negligible levels can be detected in the circulation.
T164 17957-17999 Sentence denotes ACE2, the RAAS System and Cardioprotection
T165 18000-18264 Sentence denotes After the initial discovery of ACE2 in the heart and kidney, it is now clear that it is widely distributed in tissues (section Tissue Distribution of ACE2), where it exerts many physiological effects and may be involved in pathophysiological events (Turner, 2015).
T166 18265-18471 Sentence denotes The effect of ACE2 which has been more extensively investigated is the regulation of the RAAS system, where ACE2 counter-balances ACE, limiting the potent vasoconstrictive effect of angiotensin II (Ang-II).
T167 18472-18698 Sentence denotes The first evidence that ACE2 was involved in RAAS control came from the transgenic knockout mouse model (ACE2–/–), which was characterized by severe reduction of cardiac contractility and thinning of the left ventricular wall.
T168 18699-18830 Sentence denotes Interestingly, in this knockout model disruption of the ACE pathway could rescue the myocardial phenotype (Crackower et al., 2002).
T169 18831-18966 Sentence denotes In another study, a selective ACE2 knockout model showed high blood pressure, worsened by the infusion of Ang-II (Gurley et al., 2006).
T170 18967-19105 Sentence denotes As a matter of fact, ACE2 displays its carboxypeptidase activity converting Ang-II to a heptapeptide, namely Ang1–7 (Turner et al., 2004).
T171 19106-19314 Sentence denotes ACE2 can also convert angiotensin I (Ang-I) to the non apeptide Ang1–9, which is in turn converted into Ang1–7 by ACE, competing with Ang-I and thus further decreasing Ang-II (Arendse et al., 2019; Figure 3).
T172 19315-19520 Sentence denotes Ang1–7 has been demonstrated to bind to the MasR receptor, which was initially regarded as an orphan receptor, since the use of a MasR antagonist caused inhibition of Ang1–7 effects (Alenina et al., 2008).
T173 19521-19754 Sentence denotes FIGURE 3 ACE2 signalling pathways: ACE2 displays its carboxypeptidase activity converting Ang-II (ANG II) to ANG1–7 and can also convert angiotensin I (ANG-I) to the nonapeptide Ang1–9, which is in turn converted into ANG1–7 by ACE.
T174 19755-19858 Sentence denotes ANG1-7 binds the MasR receptor to exert its effects on target organs (primarily heart, vessels, lungs).
T175 19859-19997 Sentence denotes ACE2 might also act via the bradykinin-DABK/BKB1R axis: the increased activity of the DABK axis triggers a proinflammatory cytokine storm.
T176 19998-20349 Sentence denotes In the last years the ACE2/Ang1–7/MasR system has been intensively studied: physiological effects on cardiomyocytes include modulation of Ca++ signaling and cytokine production, stimulation of cardiomyocytes progenitors and prevention of uncontrolled cell growth (Grobe et al., 2006; Flores-Muñoz et al., 2012; Souza et al., 2013; Chang et al., 2016).
T177 20350-20597 Sentence denotes Through the Ang1–7 pathway ACE2 produces endothelial antithrombotic effects, vasodilation, nitric oxide release, and inhibits vascular smooth muscle cells (VSMC) proliferation (Loot et al., 2002; Sampaio et al., 2007a,b; Fraga-Silva et al., 2008).
T178 20598-20785 Sentence denotes In preclinical studies Ang1–7 displayed antifibrotic effects, protecting from deleterious myocardial hypertrophy and modulating left ventricle remodeling after myocardial infarction (MI).
T179 20786-21120 Sentence denotes In animal models, Ang1–7 also showed an antiarrhythmic action (Ferreira et al., 2001; Santos et al., 2004; Grobe et al., 2006; Gomes et al., 2010), while compensatory ACE2 upregulation has been observed in explanted human hearts, in patients affected by ischemic or dilated cardiomyopathy (Goulter et al., 2004; Burrell et al., 2005).
T180 21121-21186 Sentence denotes Additional players contribute to ACE2-mediated cardio-protection.
T181 21187-21381 Sentence denotes Another substrate of ACE2 carboxypeptidase activity is Angiotensin A (Ang-A), identified in 2008, which has a similar, although less potent, vasopressor effect as AngII (Jankowski et al., 2007).
T182 21382-21525 Sentence denotes The product of the enzymatic reaction catalyzed by ACE2 is the peptide Ala-Ang (1–7) also known as alamandine (Lautner et al., 2013; Figure 3).
T183 21526-21661 Sentence denotes Alamandine receptor is a Mas-related G-protein coupled receptor, known as MrgD, which is expressed in cardiomyocytes and blood vessels.
T184 21662-21804 Sentence denotes MrgD knockout animals develop a severe cardiopathy and alamandine showed a cardioprotective effect in a model of sepsis (Santos et al., 2019).
T185 21805-22035 Sentence denotes Unlike ACE, ACE2 is not active on bradykinin, but it can degrade the active bradykinin metabolite des-Arg9 bradykinin (DABK), blocking the signaling pathway of the B1 bradykinin receptor (Vickers et al., 2002; Sodhi et al., 2018).
T186 22036-22143 Sentence denotes Other substrates of ACE2 include apelin-13/17, neurotensin, dynorphin A (1–13), and ghrelin (Turner, 2015).
T187 22144-22346 Sentence denotes Interestingly peptides of apelin family have been demonstrated to upregulate ACE2 expression in physiological condition and more actively during heart failure in in vivo experiments (Sato et al., 2013).
T188 22347-22611 Sentence denotes ACE2 in turn is able to regulate apelin bioavailability, establishing a negative feedback loop, and the crosstalk between RAAS, ACE2 and Apelin system might play a significant role in the pathophysiology of hypertension (Kalea and Batlle, 2010; Chen et al., 2015).
T189 22612-22966 Sentence denotes On the whole these findings suggest that ACE2 might exert antihypertensive and/or cardioprotective effects by different mechanisms, namely: (i) limiting the availability of ACE substrates, (ii) degrading Ang-II, (iii) activating the Ang1-7/MasR and/or Alamandine/MrgD pathways, (iv) interfering with other substrates, such as DABK and apelins (Figure 3).
T190 22968-22988 Sentence denotes ACE2 and Lung Injury
T191 22989-23123 Sentence denotes ACE2 is highly expressed in type I and II alveolar epithelial cells and in pulmonary small vessels (either endothelial cells or VSMC).
T192 23124-23430 Sentence denotes The hypothesis that the ACE2 arm of the RAAS system could be of benefit in lung disease derives from the observation that ACE and angiotensin II are upregulated in acute lung injury (ALI), pulmonary fibrosis, pulmonary hypertension, and acute respiratory distress syndrome (ARDS) (Imai et al., 2005, 2010).
T193 23431-23652 Sentence denotes ARDS is an overly aggressive form of ALI and it is the final mechanism of lung injury in many diseases, including sepsis, acid aspiration, pancreatitis, anthrax and virus infections (Spanish flu, H5N1 avian flu and SARS).
T194 23653-23798 Sentence denotes Imai et al. developed three ACE2 knockout mice models with severe ARDS induced by acid aspiration, endotoxin administration or peritoneal sepsis.
T195 23799-24020 Sentence denotes They showed that ARDS was accompanied by increased vessel permeability, lung oedema, and infiltration of inflammation cells, with consequent impairment of respiratory function (Imai et al., 2005, 2007; Kuba et al., 2006).
T196 24021-24165 Sentence denotes The phenotype was dramatically improved and rescued either administering ACE2 recombinant analogs or AT1Ra inhibitors (Imai et al., 2005, 2008).
T197 24166-24416 Sentence denotes ACE2 may also reduce lung inflammation via Ang1–7/MasR, since treatment with recombinant Ang1–7 in a model of allergic asthma reduced eosinophil mobilization, peri-bronchial inflammation, fibrosis and goblet cells metaplasia (El-Hashim et al., 2012).
T198 24417-24615 Sentence denotes An anti-inflammatory effect with reduction of airway remodeling has also been demonstrated in another model of chronic asthma, after administration of Ang1–7 analog (Rodrigues-Machado et al., 2013).
T199 24616-24838 Sentence denotes The underlying mechanism seems to be the modulation of the so-called cytokine storm and particularly the inhibition of transforming growth factor β (TGF- β) and NFkB signaling pathways (Li et al., 2015; Meng et al., 2015).
T200 24839-24917 Sentence denotes ACE2 might also modulate lung inflammation via the bradykinin-DABK/BKB1R axis.
T201 24918-25137 Sentence denotes In fact, decreased ACE2 function in mouse lungs caused increased activity of the DABK axis and triggered a proinflammatory cytokine storm (CXCL5, MIP2, KC, and TNF-α), leading to pulmonary collapse (Sodhi et al., 2018).
T202 25138-25201 Sentence denotes In human, ACE/ACE2 imbalance may be related to genetic factors.
T203 25202-25426 Sentence denotes In particular, a specific polymorphism of the ACE gene, namely ACE D, which determines increased ACE activity and decreased ACE2 activity has been correlated to ARDS susceptibility and mortality rate (Marshall et al., 2002).
T204 25427-25647 Sentence denotes More recently, high levels of angiotensin II have been reported in patients infected with avian influenza viruses H5N1 and H7N9, and they were strongly predictive of a poor outcome (Huang et al., 2014; Zou et al., 2014).