LitCovid-sentences  

PMC:7408073 / 13774-27628 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T66 0-2 Sentence denotes 3.
T67 3-52 Sentence denotes Pathological Effects of ACE2 Pathway Upregulation
T68 53-175 Sentence denotes ACE and ACE2 are two zinc metalloproteases involved in the biogenesis of the components of renin-angiotensin system (RAS).
T69 176-376 Sentence denotes ACE2 processes angiotensin (Ang) I and II into Ang (1–9) and Ang (1–7), respectively, and it also has other known peptide targets, such as des-Arg(9)-bradykinin, which mediates B1 receptor activation.
T70 377-723 Sentence denotes Ang (1–7) and Ang (1–9) peptides, opposing the effects of ACE/Ang II/Ang II type 1 receptor (AT1R) pathway, are known to mediate vasodilatative (hypotension), antiproliferative and apoptotic effects through Mas and AT2 receptors, respectively, both involving downstream nitric oxide synthase (NOS) pathway activation [38,39,40,41,42,43,44,45,46].
T71 724-879 Sentence denotes Physiology teaches us that there is a range of normality for every biological parameter, below (defect) and above (excess) of which there is a dysfunction.
T72 880-934 Sentence denotes This is likely to be true for ACE as well as for ACE2.
T73 935-1149 Sentence denotes It is well known that excessive Ang II/AT1R pathway activation induces vasoconstriction, aldosterone, inflammation, excessive cell proliferation, thrombosis, cardiac dysfunction and lung alterations (see Figure 1).
T74 1150-1442 Sentence denotes Moreover, most of the experiments show that increased ACE2 activity leads to beneficial effects; however, the experiments were usually performed using models in which its “antagonist“ (ACE) pathway was upregulated or ACE2 itself was downregulated, therefore balancing an unbalanced situation.
T75 1443-1502 Sentence denotes What does it happen in models in which the opposite occurs?
T76 1503-1714 Sentence denotes (s)ACE2 or Ang (1–7) upregulation have been associated to some pathological conditions such as inflammation of the renal and gastrointestinal tract, cardiac dysfunction, human cirrhosis and lung injury/fibrosis.
T77 1715-1878 Sentence denotes Tissue/organ specific effects of excessive pathway activation that in some case resemble those produced by excessive Ang II/AT1R pathway activation (see Figure 1).
T78 1879-2018 Sentence denotes For example, systemic infusion of Ang (1–7) into mice had renal proinflammatory properties mediated by Mas receptor (MasR) activation [47].
T79 2019-2169 Sentence denotes Moreover, Ang (1–7) infusion was associated with increases in blood pressure, cardiac hypertrophy and fibrosis in rats with subtotal nephrectomy [48].
T80 2170-2350 Sentence denotes Similarly, elevated plasma sACE2 activity was associated both with greater severity of myocardial dysfunction and with an independent prediction of adverse clinical events [22,49].
T81 2351-2611 Sentence denotes Transgenic mice with increased cardiac ACE2 expression suffered from lethal ventricular arrhythmia (heart block, ventricular tachycardia and terminal ventricular fibrillation) consequent upon downregulation of connexins involved in gap junction formation [50].
T82 2612-2760 Sentence denotes In another model, ACE2 transgenic mice suffered from cardiac fibrosis with concomitant deficits in ejection fraction and fractional shortening [51].
T83 2761-3154 Sentence denotes Interestingly, in a rat model of myocardial infarction following coronary artery ligation, there is evidence that C16/MLN-4760 (a specific ACE2 inhibitor, see later) administration inhibits fibrosis and hypertrophy of non-infarcted myocardium and increases diastolic relaxation, raising the possibility that ACE2 activity may have some adverse effects on post-myocardial infarction heart [52].
T84 3155-3293 Sentence denotes The risk factors for cardiovascular disease include alterations in platelet function and coagulation with an increased risk of thrombosis.
T85 3294-3470 Sentence denotes Ang II and hypercholesterolemia are known to participate in microvascular thrombosis and enhanced thrombus formation in the microvasculature may contribute to microinfarctions.
T86 3471-3667 Sentence denotes To this end, in a rat model in which AT1R activation produce baseline thrombosis by platelet aggregation, Ang (1–9), known to bind AT2R [42], has been shown to enhance the thrombotic process [53].
T87 3668-3977 Sentence denotes Moreover, in a mouse model, AT2R activation (inhibited by AT2R antagonist, PD12319) mediated the onset of arteriolar microvascular thrombosis following chronic Ang II infusion [54], indicating both the recruitment of the AT2R pathway downstream of AT1R activation and its involvement in arteriolar thrombosis.
T88 3978-4287 Sentence denotes Of interest, disseminated intravascular coagulation is associated with hypoproteinaemia and deficit of coagulation and anticoagulation proteins, which can originate by their renal loss (and consequent proteinuria) and/or by their increased (pathological) consumption and/or by their reduced hepatic synthesis.
T89 4288-4496 Sentence denotes To this end, in healthy livers, ACE2 is limited to perivenular hepatocytes and endothelial cells; instead, in human hepatitis C cirrhosis, ACE2 protein expression is widespread in the hepatic parenchyma [55].
T90 4497-4688 Sentence denotes Notably, human hepatocytes cultured in hypoxic conditions upregulated ACE2 protein expression [55] and ACE2 mRNA, protein and activity were increased in response to hypoxia and by IL-1β [56].
T91 4689-4892 Sentence denotes In line with these observations, in peripheral blood human CD34+ cells, MasR expression and ACE2 expression, activity and shedding (of sACE2 catalytically active forms) were increased under hypoxia [57].
T92 4893-5150 Sentence denotes Moreover, under hypoxic conditions human pulmonary artery smooth muscle cells upregulated both (arms of the RAS) ACE and ACE2 mRNA and protein expression, and ACE2 was subsequently downregulated by (ACE-derived) Ang II through an AT1R-mediated process [58].
T93 5151-5336 Sentence denotes Similarly, both ACE and ACE2 expression were increased in vascular endothelium and smooth muscle of human left ventricle from patients with ischaemic (local hypoxia) heart disease [59].
T94 5337-5459 Sentence denotes Concomitant upregulation of both arms of the RAS that suggests a tight link between ACE and ACE2 under hypoxic conditions.
T95 5460-5598 Sentence denotes Indeed, several reports have shown a complex interplay of regulation between the two arms of the RAS independently on hypoxia (see Box 2).
T96 5599-6136 Sentence denotes Interestingly, chronic hypoxia induced activation of ACE2/Ang (1–7)/MasR axis and suppression of ACE/Ang II/AT1 receptor axis in lungs of pulmonary hypertensive Ren-2 transgenic rats (constructed by inserting the mouse Ren-2 renin gene) but not in normotensive transgene-negative control rats [60], suggesting that the baseline renin activity in hypertensive rats may be crucial to determine the differential response to hypoxia and that renin inhibition might be useful to inhibit the ACE to ACE2 pathway shift under hypoxic conditions.
T97 6137-6312 Sentence denotes Of interest, hypoxia alone or combined with hypercapnia has been shown to significantly increase both plasma renin expression or activity and plasma Ang II expression [61,62].
T98 6313-6808 Sentence denotes Moreover, hypercapnic acidosis (pH 6.8/6.9, a condition that could occur in SARS) induced in isolated rat lungs has been shown to induce a (compensatory) venular dilatation mediated by cyclooxygenase activation (inhibited by indomethacin) [63], an enzyme that has been shown to be induced downstream of Ang (1–7)/MasR pathway in isolated rat hearts (again inhibited by indomethacin) [64], suggesting the involvement of ACE2/Ang (1–7) pathway in mediating CO2-dependent lung venular vasodilation.
T99 6809-7204 Sentence denotes Altogether these observations indicate that there is a high probability that hypoxia/hypercapnia, a condition that occurs in SARS patients, might upregulate the activity of both arms of the RAS by suppling high amounts of renin product, Ang I, to ACE and ACE2, which, together, can produce high amounts of Ang II, Ang (1–9), Ang (1–7) and its (ACE-produced) metabolite, Ang (1–5) (see Figure 1).
T100 7205-7490 Sentence denotes Similarly to both Ang (1–7)/MasR and Ang (1–9)/AT2R pathways, Ang (1–5) has been shown to induce the secretion of atrial natriuretic peptide via MasR/NOS pathway in isolated perfused rat atria [65], indicating that Ang (1–5) is a heart active peptide (at least in Sprague-Dawley rats).
T101 7491-7657 Sentence denotes Interestingly, in the plasma of patients with inflammatory bowel disease, Ang (1–7) concentrations and (s)ACE2 activity were higher compared to healthy subjects [66].
T102 7658-7811 Sentence denotes Moreover, Ang (1–7) alone can either activate the Bax/Caspase–dependent apoptotic pathway or upregulate NF-kB signaling in lung fibroblast cultures [67].
T103 7812-8085 Sentence denotes Moreover, in vivo administration of Ang (1–7) alone (in Wistar rats) promoted morphological lung alterations, extracellular matrix accumulation and inflammatory cytokine production (including TNF-α and IL-6), characteristics of lung inflammation in pulmonary fibrosis [67].
T104 8086-8183 Sentence denotes Thereby, a condition that deteriorates respiratory compliance, could lead to hypoxia/hypercapnia.
T105 8184-8395 Sentence denotes Hypoxia, in turn, will induce ACE2 upregulation which possibly increases cardiac/lung detrimental effects mediated by Ang (1–7)/MasR pathway activation finally leading to further ACE2 cell membrane upregulation.
T106 8396-8631 Sentence denotes A condition that in COVID-19 can increase the probability of both SARS-CoV-2 entry and ACE2 shedding/systemic activity, finally generating positive feedback loops that might sustain SARS independently of viral infection (see Figure 2).
T107 8632-8949 Sentence denotes This hypothesis is supported by the observations that, in lung aspirates of acid- and/or spike-treated mice, Ang II and ACE2 are synergistically upregulated and cell surface downregulated (shed), respectively, suggesting their involvement in the increased lung microvascular permeability and pulmonary oedema [14,15].
T108 8950-9157 Sentence denotes Indeed, this condition might subsequently favour the diffusion, in neighbouring lung tissues and systemic circulation, of both (s)ACE2, Ang II and Ang (1–7), the Ang II-derived product of (s)ACE2 processing.
T109 9158-9347 Sentence denotes As already proposed, enhanced ACE2 shedding may locally reduce ACE2 activity in lung, however, it likely increases ACE2 systemic activity and subsequent production of circulating Ang (1–7).
T110 9348-9485 Sentence denotes Interestingly, Ang (1–7) has been also reported to promote eosinophil apoptosis in lungs and in bronco-alveolar lavage fluid (BALF) [40].
T111 9486-9757 Sentence denotes Moreover, Ang (1–7)/MasR axis inhibits allergic airway inflammation and eosinophil cell counts in the BALF of a murine model of asthma, indicating both that an impairment of ACE2 pathway may favour asthma and that ACE2 pathway activation can reduces asthma symptoms [68].
T112 9758-9989 Sentence denotes Moreover, a compound that mimics the Ang (1–7) actions has been shown to induce IL-10 upregulation via a MasR-dependent pathway in BALF [69] and IL-10 is thought to mediate anti-inflammatory effects of MasR pathway activation [70].
T113 9990-10110 Sentence denotes IL-10 secretion in mouse plasma was also induced by an AT2 receptor agonist and downstream nitric oxide signalling [71].
T114 10111-10304 Sentence denotes Increased IL-10 production (e.g., by T regulatory cells) is often associated with immune tolerance, which is the consequence of reduced number and function of specific immune compartments [72].
T115 10305-10665 Sentence denotes Indeed, IL-10 has been shown not only to suppress antigen-specific Th2-mediated immune responses including eosinophil expansion in allergic inflammation [72], but also to augment airway reactivity, suggesting that despite its potent anti-inflammatory activity, an excess of IL-10, as well as Ang (1–7), may contribute to the decline in pulmonary function [73].
T116 10666-10978 Sentence denotes Of note, IL-10 is one of the cytokines downstream ACE2 pathway [25] and is significantly upregulated in the most severe forms of COVID-19 [2,8,9], indicating an important correlation between ACE2/Ang (1–7) axis activation and IL-10 upregulation which might lead to eosinopaenia/lymphopaenia in COVID-19 patients.
T117 10979-11050 Sentence denotes Box 2 The reciprocal feedback-loop mechanisms of both arms of the RAS.
T118 11051-11383 Sentence denotes Similarly to hypoxic conditions, a strong correlation between the gene expression of ACE and that of ACE2 was also observed in human renal cortical biopsy specimen, suggesting a link between the two gene transcription, possibly related to the amount/excess of their substrates (Ang I and Ang II) and not exclusively to hypoxia [74].
T119 11384-11744 Sentence denotes A link that tends to maintain the balance of ACE/ACE2 ratio, but that may be disrupted by ACE inhibitors (ACEIs) or by Ang II type 1 receptor blockers (ARBs) which both have been shown to upregulate ACE2 mRNA expression in left ventricle of Lewis rats, possibly through two different mechanisms involving upregulation of Ang (1–7) or Ang II, respectively [75].
T120 11745-12010 Sentence denotes In this regard, in cardiac myocytes isolated from neonatal rats, Ang II significantly reduced ACE2 mRNA and its activity, effects blocked by ARBs, indicating that Ang II downregulates ACE2 expression/activity through an AT1R-dependent mechanism [76] (see Figure 1).
T121 12011-12365 Sentence denotes Moreover, in both cardiac myocytes and rat aortic vascular smooth muscle cells, Ang (1–7) prevented the Ang II-mediated reduction in ACE2 mRNA, an effect blocked by a selective MasR antagonist, D-Ala7-Ang-(1–7) (also known as A779), indicating that Ang (1–7) downregulates Ang II/AT1R signalling through a MasR-dependent mechanism [76,77] (see Figure 1).
T122 12366-12709 Sentence denotes Therefore, Ang (1–7) (as well as ACEIs and ARBs), preventing Ang II-mediated ACE2 downregulation, shift the Ang peptide balance in favour of Ang II metabolisation by ACE2, which, in turn, leads to further production of Ang (1–7), finally sustaining ACE2 transcription, membrane protein expression and eventually shedding and systemic activity.
T123 12710-12921 Sentence denotes Altogether these observations indicate a complex interplay of regulation between the two arms of the RAS in which feedback mechanisms of reciprocal (ACE/ACE2) pathway inhibition are involved at different levels:
T124 12922-13109 Sentence denotes Ang II/AT1 receptor mediates a negative feedback signal on the ACE2 expression/activity and Ang (1–7)/MasR mediated a negative feedback signal on the AT1 receptor activity (see Figure 1).
T125 13110-13340 Sentence denotes These reciprocal inhibitions in some cases (e.g., hypoxia/SARS-CoV-2 infection) can give rise to positive feedback loops that markedly shift the balance between Ang II/AT1R and the antagonist Ang (1–7)/MasR pathway (see Figure 1).
T126 13341-13638 Sentence denotes For example, under hypoxic conditions both arms of the RAS are upregulated and the presence of SARS-CoV-2 can affect Ang (1–7)/Ang II balance (which might be further influenced by ACEI/ARBs) by shifting it in favour of an increased ACE2 systemic activity, Ang (1–7) production and MasR activation.
T127 13639-13854 Sentence denotes This, in turn, can lead to further ACE2 cell membrane expression (increasing the probability of viral entry), which, after ACE2 shedding by binding to spike-SARS-CoV-2, ultimately establish a positive feedback loop.