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CORD-19:f22ac602926d152936dd6af839da45bf8290e038 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T1 0-131 Sentence denotes Devil and angel in the renin-angiotensin system: ACE-angiotensin II-AT 1 receptor axis vs. ACE2-angiotensin-(1-7)-Mas receptor axis
T2 133-141 Sentence denotes Abstract
T3 142-234 Sentence denotes Recent studies have established a new regulatory axis in the renin-angiotensin system (RAS).
T4 235-382 Sentence denotes In this axis, angiotensin (Ang)-(1-7) is finally produced from Ang I or Ang II by the catalytic activity of angiotensin-converting enzyme 2 (ACE2).
T5 383-573 Sentence denotes Ang-(1-7) shows actions different from those of AT 1 receptor stimulation, such as vasodilatation, natriuresis, anti-proliferation and an increase in the bradykinin-NO (nitric oxide) system.
T6 574-789 Sentence denotes As the catalytic efficiency of ACE2 is approximately 400-fold higher with Ang II as a substrate than with Ang I, this axis is possibly acting as a counter-regulatory system against the ACE/Ang II/AT 1 receptor axis.
T7 790-887 Sentence denotes The signaling pathway of the ACE2-Ang-(1-7) axis has not yet been totally and clearly understood.
T8 888-977 Sentence denotes However, a recent report suggests that the Mas oncogene acts as a receptor for Ang-(1-7).
T9 978-1031 Sentence denotes Intracellular signaling through Mas is not clear yet.
T10 1032-1205 Sentence denotes Several factors such as Akt phosphorylation, protein kinase C activation and mitogen-activated protein (MAP) kinase inhibition seem to be involved in this signaling pathway.
T11 1206-1312 Sentence denotes Further investigations are needed to clarify the regulation and mechanism of action of ACE2 and Ang-(1-7).
T12 1313-1458 Sentence denotes However, this second axis through ACE2 and Ang-(1-7) in RAS can be an important target for the therapy of cardiovascular and metabolic disorders.
T13 1460-1544 Sentence denotes The renin-angiotensin system (RAS) has a critical role in the cardiovascular system.
T14 1545-1646 Sentence denotes Recent studies on RAS have found various components and have proposed new axes of signaling pathways.
T15 1647-1784 Sentence denotes In a classical system, angiotensin (Ang) II produced from Ang I by an angiotensinconverting enzyme (ACE) is a strong bioactive substance.
T16 1785-2119 Sentence denotes Ang II binds to two major types of receptors, namely, Ang II type 1 (AT 1 ) and Ang II type 2 (AT 2 ) receptors, 1 the signaling pathways of which have been well studied, including in the identification of new signalingrelated molecules, such as AT 1 receptor-associated protein (ATRAP) 2 and AT 2 receptor-interacting protein (ATIP).
T17 2120-2254 Sentence denotes 3 In cardiovascular diseases, AT 2 -receptor stimulation seems to antagonize the signaling associated with AT 1 -receptor stimulation.
T18 2255-2481 Sentence denotes As the binding affinity of Ang II for the AT 2 receptor does not differ from that for the AT 1 receptor, it is considered that AT 2 -receptor stimulation contributes to the beneficial actions of AT 1 -receptor blockers (ARBs).
T19 2482-2664 Sentence denotes 4 In this context, AT 2 -receptor agonists, such as compound 21, have been newly developed and are expected to function as useful agents against pathological disorders in the future.
T20 2665-2716 Sentence denotes 5 Recently, a new axis of RAS has been established.
T21 2717-2805 Sentence denotes In this axis, Ang I is finally converted to Ang-(1-7) by the catalytic activity of ACE2.
T22 2806-2902 Sentence denotes 6, 7 The mechanisms of action of Ang-(1-7) are still being investigated by many research groups.
T23 2903-2916 Sentence denotes Santos et al.
T24 2917-2978 Sentence denotes 7 reported that the Mas oncogene is a receptor for Ang-(1-7).
T25 2979-3089 Sentence denotes There are an increasing number of reports on the role of ACE2, Ang-(1-7) and Mas in the cardiovascular system.
T26 3090-3253 Sentence denotes In this review, an outline of the role and function of ACE2 with the Ang-(1-7) pathway is discussed in comparison with the classical ACE-Ang II-AT 1 receptor axis.
T27 3254-3342 Sentence denotes Ang II is a well-known bioactive substance involved in the regulation of blood pressure.
T28 3343-3408 Sentence denotes Ang II is involved in the exaggeration of cardiovascular disease.
T29 3409-3513 Sentence denotes 4 Recent studies indicate that Ang II is also involved in the onset of diabetes and metabolic disorders.
T30 3514-3585 Sentence denotes 8 In classical RAS, Ang II is produced from Ang I by the action of ACE.
T31 3586-3656 Sentence denotes This classical axis can be called as the ACE-AngII-AT 1 receptor axis.
T32 3657-3763 Sentence denotes Such findings are closely related to the development of RAS inhibitors, such as the ACE inhibitor and ARB.
T33 3764-3835 Sentence denotes The major receptor subtypes for Ang II are the AT 1 and AT 2 receptors.
T34 3836-3980 Sentence denotes The AT 1 receptor was cloned in 1991, and this finding has contributed to the development of ARBs and accelerated basic and clinical researches.
T35 3981-4162 Sentence denotes 9 The distribution of the AT 1 receptor covers most organs, whereas AT 2 -receptor expression is observed in only a few organs after birth and is upregulated in pathological states.
T36 4163-4371 Sentence denotes 1 AT 1 -receptor stimulation mediates the classical major actions of Ang II, and large clinical trials and basic researches have established the concept of the cardiovascular continuum proposed by Dzau et al.
T37 4372-4506 Sentence denotes 10, 11 AT 1receptor stimulation is in fact known to exert hypertension, stroke, cardiovascular events and renal diseases ( Figure 1 ).
T38 4507-4587 Sentence denotes It has also been reported that the blockade of AT 1 receptor promotes longevity.
T39 4588-4670 Sentence denotes 12 In recent years, efforts have been carried out to produce the inhibitor of RAS.
T40 4671-4796 Sentence denotes The first trial to produce a renin inhibitor did not succeed for clinical use because of chemical and technical difficulties.
T41 4797-4847 Sentence denotes However, these efforts produced the ACE inhibitor.
T42 4848-4909 Sentence denotes This success triggered the development of new RAS inhibitors.
T43 4910-4969 Sentence denotes ACE inhibitors have some adverse effects, such as coughing.
T44 4970-5130 Sentence denotes In addition, chronic administration of an ACE inhibitor showed an escape phenomenon, in which the inhibitory action of the ACE inhibitor is strongly attenuated.
T45 5131-5206 Sentence denotes To solve such problems, ARB has been developed as the second RAS inhibitor.
T46 5207-5397 Sentence denotes As most actions of Ang II are mediated through the AT 1 receptor, the non-peptide ARB is available and widely used in the treatment of hypertension, and in cardiovascular and renal diseases.
T47 5398-5476 Sentence denotes Ang II acts mainly through AT 1 receptors, using various signaling mechanisms.
T48 5477-5602 Sentence denotes For example, AT 1 -receptor stimulation increases the influx of extracellular Ca 2+ and mobilization of intracellular Ca 2+ .
T49 5603-5856 Sentence denotes An increase in the intracellular Ca 2+ level activates acute responses, such as vascular smooth-muscle contraction, and also activates various kinases, including the mitogen-activated protein (MAP) kinase pathway, to induce cell-proliferation signaling.
T50 5857-5942 Sentence denotes AT 1 -receptor stimulation seems to activate the EGF receptor in the plasma membrane.
T51 5943-6090 Sentence denotes Therefore, a part of the action caused by AT 1 -receptor stimulation is similar to that caused by Ca 2+ -mobilizing hormones and by the EGF family.
T52 6091-6191 Sentence denotes In contrast, signaling mediated by AT 2 -receptor stimulation is transferred mainly by phosphatases.
T53 6192-6320 Sentence denotes 1 Therefore, the action of AT 2 -receptor stimulation is considered to be antagonized against AT 1 -receptor-mediated signaling.
T54 6321-6733 Sentence denotes In fact, an antagonizing action or the counter-regulation of AT 2 -receptor stimulation has been reported previously. [13] [14] [15] ROLES OF ACE2, ANG-(1-7) AND THE MAS AXIS-A NEW RAS PATHWAY Possible effects such as vasodilation mediated by Ang-(1-7) have been reported; however, the mechanisms leading to Ang-(1-7) production and its receptor were unclear, resulting in the delay of Ang-(1-7)based researches.
T55 6734-6798 Sentence denotes Recent reports show that Ang-(1-7) is produced by ACE2 activity.
T56 6799-6878 Sentence denotes 16, 17 ACE2 is reported to be highly expressed in the heart, kidney and testis.
T57 6879-6992 Sentence denotes ACE2 is a membrane-associated hydrolase and it hydrolyzes Ang I to Ang-(1-9) and Ang II to Ang-(1-7) (Figure 2 ).
T58 6993-7133 Sentence denotes 18 As Ang-(1-9) can be converted to Ang-(1-7) by ACE or by other peptidases, ACE2 facilitates Ang-(1-7) production by two separate pathways.
T59 7134-7185 Sentence denotes 19 Ang-(1-7) loses only one amino acid from Ang II.
T60 7186-7306 Sentence denotes It might be possible that Ang-(1-7) is a degradation product of Ang II and one of the inactivation mechanisms of Ang II.
T61 7307-7384 Sentence denotes However, recent studies indicate that Ang-(1-7) has more active roles in RAS.
T62 7385-7487 Sentence denotes Ang-(1-7) causes vasodilation, which antagonizes AT 1 -receptor stimulation-mediated vasoconstriction.
T63 7488-7566 Sentence denotes This effect seemed to be mediated by the bradykinin-NO (nitric oxide) pathway.
T64 7567-7925 Sentence denotes 18, 20 Accordingly, these results suggest that Ang-(1-7) antagonized the pressor effect of AT 1 -receptor stimulation, suggesting that it may act as a kind of AT 1 -receptor antagonist, thereby resulting in a blood-pressure-lowering effect and an organ-protective effect, such as a reduction of cardiac hypertrophy and fibrosis and renal damage ( Figure 3 ).
T65 7926-8023 Sentence denotes It is reported that a lack of ACE2 accelerates the pressure-overload-induced cardiac dysfunction.
T66 8024-8149 Sentence denotes 21 On the other hand, the Ang-(1-7) agonist, Figure 1 The role of AT 1 receptor stimulation in hypertension and organ damage.
T67 8150-8196 Sentence denotes NO, nitric oxide; CKD, chronic kidney disease.
T68 8197-8279 Sentence denotes The production of angiotensin-(1-7) by the angiotensin-converting enzyme 2 (ACE2).
T69 8280-8349 Sentence denotes M Iwai and M Horiuchi AVE0991, was cardioprotective in diabetic rats.
T70 8350-8662 Sentence denotes 22 In addition, Ang-(1-7) potentiates bradykinin, either through an AT 2 -receptordependent mechanism or through the inhibition of ACE. [23] [24] [25] Recent studies have also shown that Ang-(1-7), similar to ACE inhibitors, potentiates the effect of bradykinin by inhibiting the desensitization of its receptor.
T71 8663-8902 Sentence denotes 26, 27 It has been discovered that the catalytic efficiency of ACE2 is approximately 400-fold higher with Ang II as a substrate than with Ang I, 17 suggesting that this second arm of the system acts as a counter-regulator of the first arm.
T72 8903-9038 Sentence denotes Previous reports suggest that olmesartan, an ARB, increased the plasma concentration of Ang-(1-7) and the cardiac ACE2expression level.
T73 9039-9222 Sentence denotes 28, 29 Another ARB, losartan, also induced similar changes; however, its dose was 100-fold higher than that of olmesartan, 28 suggesting that this effect of ARB is not a class effect.
T74 9223-9361 Sentence denotes A more detailed analysis could show the regulation of ACE2 and Mas, which could contribute toward a new drug discovery for regulating RAS.
T75 9362-9552 Sentence denotes Recent studies on the function of ACE2 suggest that ACE2 has an important role in the severity of lung failure, such as in acute respiratory distress syndrome (ARDS) or in acute lung injury.
T76 9553-9784 Sentence denotes 30 Moreover, it has been shown that the severe acute respiratory syndrome (SARS) corona virus utilizes ACE2 as an essential receptor for cell fusion and for in vivo infections, suggesting that ACE2 contributes to SARS pathogenesis.
T77 9785-9940 Sentence denotes 31 These results indicate that ACE2 activity has an important role not only in cardiovascular diseases but also in damages or dysfunctions of other organs.
T78 9941-10070 Sentence denotes We can expect the further studies on ACE2 functions to contribute toward a new therapy for organ damages that target this enzyme.
T79 10071-10151 Sentence denotes A recent report suggests that the Mas oncogene acts as a receptor for Ang-(1-7).
T80 10152-10239 Sentence denotes 32, 33 Mas is a class of G-protein-coupled receptor containing 325 amino-acid residues.
T81 10240-10310 Sentence denotes The expression of Mas is abundantly expressed in the brain and testis.
T82 10311-10462 Sentence denotes Low levels of Mas expression were also observed in other tissues, such as in the heart, kidney, lung, liver, spleen, tongue and in the skeletal muscle.
T83 10463-10565 Sentence denotes 34, 35 The studies using The balance between ACE and ACE2 activities affects cardiovascular disorders.
T84 10566-10697 Sentence denotes ACE, angiotensin-converting enzyme; Ang, angiotensin; AT 1 , angiotensin-II type-1 receptor; AT 2 , angiotensin-II type-2 receptor.
T85 10698-10773 Sentence denotes Mas-deficient mice showed an impairment of cardiac functions in these mice.
T86 10774-10948 Sentence denotes 36, 37 Recent studies suggest that Rac 1, c-Jun NH 2 -terminal kinase (JNK), p38 MAP kinase and the activation of phospholipase C might be involved in Mas-mediated signaling.
T87 10949-11051 Sentence denotes One of the major pathways of Mas signaling in the cardiovascular system is the phosphorylation of Akt.
T88 11052-11190 Sentence denotes Moreover, in cardiomyocytes, an inhibition of MAP kinase activation by Ang-(1-7) can be blocked by antisense oligonucleotides against Mas.
T89 11191-11263 Sentence denotes 38 More detailed research works can show the Mas functions more clearly.
T90 11264-11449 Sentence denotes In recent years, several classes of RAS inhibitors have been developed and these inhibitors are effective in hypertensive patients and in hypertension-associated pathological disorders.
T91 11450-11540 Sentence denotes ACE inhibitors, ARBs and renin inhibitors are already available for hypertensive patients.
T92 11541-11631 Sentence denotes Moreover, the AT 2 -receptor agonists, such as compound 21, could be useful in the future.
T93 11632-11748 Sentence denotes In previous studies, the detailed mechanism of the regulation of the ACE2-Ang-(1-7)-Mas axis was not clearly stated.
T94 11749-11879 Sentence denotes However, it has been clarified that this pathway acts as a counter-regulation system against the ACE-Ang II-AT 1 receptor pathway.
T95 11880-12068 Sentence denotes Therefore, it is suggested that the ACE2-Ang-(1-7)-Mas axis could become a new target for the therapy of circulatory disorders and adult diseases, including that of the metabolic syndrome.
T96 12069-12168 Sentence denotes The total effects of RAS seem to stand on the balance between ACE and ACE2 activities ( Figure 4) .
T97 12169-12408 Sentence denotes In this respect, it could be considered that the classical ACE-Ang II-AT 1 receptor axis plays as a 'devil' and the 'ACE2-Ang-(1-7)-Mas axis' plays as an angel for fruitful aging in RAS through blood pressure lowering and organ protection.
T98 12409-12453 Sentence denotes The authors declare no conflict of interest.