Epistemic_Statements  

CORD-19:2c8a8461d046eeda9f76e88e5db50af4af949e22 JSONTXT 8 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T1 0-63 Epistemic_statement denotes ACE2, a Promising Therapeutic Target for Pulmonary Hypertension
T2 74-190 Epistemic_statement denotes Pulmonary arterial hypertension (PAH) is a chronic lung disease with poor diagnosis and limited therapeutic options.
T3 467-578 Epistemic_statement denotes An altered renin-angiotensin system (RAS) has been implicated as a causative factor in the pathogenesis of PAH.
T4 579-795 Epistemic_statement denotes Angiotensin II, a key effector peptide of the RAS, can exert deleterious effects on the pulmonary vasculature resulting in vasoconstriction, proliferation and inflammation, all of which contribute to PAH development.
T5 1043-1178 Epistemic_statement denotes ACE2 is abundantly expressed in the lung tissue and emerging evidence suggests a beneficial role for this enzyme against lung diseases.
T6 1575-1707 Epistemic_statement denotes However, in PAH, the resting mean pulmonary arterial pressure measures over 25mm Hg (and greater than 30mm Hg during exercise) [1] .
T7 1708-1897 Epistemic_statement denotes PAH can either be of idiopathic origin with unknown etiology or, it can arise due to secondary medical conditions such as collagen vascular diseases, heart malformation or viral infections.
T8 1898-1981 Epistemic_statement denotes Genetic and epigenetic risk factors have also been linked to PAH pathogenesis [2] .
T9 1982-2112 Epistemic_statement denotes Regardless of the cause, PAH is associated with endothelial dysfunction, vasoconstriction and remodeling of the pulmonary vessels.
T10 2113-2363 Epistemic_statement denotes Endothelial dysfunction is believed to be an early component of the pulmonary hypertensive process, creating an imbalance between vasodilator (nitric oxide, prostacyclin) and vasoconstrictor substances (endothelin, thromboxane A2 and serotonin) [3•].
T11 2998-3170 Epistemic_statement denotes Conversely, ACE2, the recently discovered homologue of ACE has been shown to oppose the detrimental effects of the ACE-AngII-AT1R axis on the cardio-pulmonary system [6••].
T12 3171-3392 Epistemic_statement denotes This review focuses on the role of ACE2 in the pathobiology of pulmonary hypertension and provides proof of concept that targeting of this enzyme can prove to be an effective therapeutic strategy for the treatment of PAH.
T13 4006-4131 Epistemic_statement denotes Several new members of the RAS have recently been identified, which has expanded our understanding of this biological system.
T14 4132-4278 Epistemic_statement denotes These new members include (pro) renin receptor [8] , Angiotensin-(1-12) [9] , ACE2 ([10] [11] , Angiotensin-(1-7) [12] and the Mas receptor [13] .
T15 4431-4583 Epistemic_statement denotes It is relevant to point out that polymorphism in the genes encoding for Angiotensinogen [14] , and ACE [15] , has been linked to the development of PAH.
T16 4805-4953 Epistemic_statement denotes The deletion allele (DD) is associated with increased ACE activity, while the insertion allele (II) is associated with decreased ACE activity [17] .
T17 4954-5081 Epistemic_statement denotes The ACE DD genotype, accompanied by elevated circulating levels of Ang II, has been implicated in the development of PAH [18] .
T18 5082-5272 Epistemic_statement denotes Interestingly, the lungs of pulmonary hypertensive patients as well as animals with PAH express high levels of ACE, suggesting a causative role for this enzyme in disease pathogenesis [19] .
T19 5784-5921 Epistemic_statement denotes Accumulating evidence also suggests that Ang II induces apoptosis of the lung parenchymal cells, leading to pulmonary hypertension [24] .
T20 5922-6029 Epistemic_statement denotes Collectively, these findings clearly indicate an active role for RAS in the pulmonary hypertensive process.
T21 6030-6212 Epistemic_statement denotes However, pharmacological blockade with ACE inhibitors or AT1R antagonists have produced mixed results against PAH [25] [31] , thus rendering their medical use somewhat controversial.
T22 6213-6553 Epistemic_statement denotes Nevertheless, several lines of emerging evidence strongly suggest that the recently discovered ACE homologue, ACE2, either by itself or through its catalytic product Ang-(1-7) opposes the proliferative, hypertrophic and fibrotic effects of Ang II [32] in many organs, including the lungs, suggesting a plausible protective role against PAH.
T23 6788-6945 Epistemic_statement denotes However, unlike ACE, which is a dipeptidyl-peptidase, ACE2 is a mono-carboxypeptidase that cleaves a single amino acid from the C-terminal of its substrates.
T24 6946-7060 Epistemic_statement denotes Ang II appears to be the main substrate for ACE2, and is effectively hydrolyzed to Angiotensin-(1-7) [Ang-(1-7) ].
T25 7686-7760 Epistemic_statement denotes ACE2 has been suggested to play an important role in lung pathophysiology.
T26 7761-8556 Epistemic_statement denotes Evidence for this comes from the following observations: 1) decreased expression of ACE2 is associated with lung fibrosis in both human and experimental animals [37] ; 2) lung overexpression of ACE2 attenuates monocrotaline-induced pulmonary hypertension [38] and bleomycininduced pulmonary fibrosis [39] ; 3) ACE2 protects murine lungs from acute injury [40] and respiratory distress syndrome [41] ; 4) mutant ACE2 mice exhibit enhanced vascular permeability with declining lung function [42] ; 5) reduced pulmonary ACE2 expression due to SARS-CoV infection results in lung failure [43] ; 6) administration of recombinant ACE2 prevents the development of lung failure in ACE2 knockout mice [42] ; and 7) ACE2 treatment reversed established pulmonary arterial hypertension in BMPR2R899X mice (J.
T27 8631-8779 Epistemic_statement denotes A recent report by Takahashi et al., [44] also suggests that auto-antibodies to ACE2 may predispose patients with connective tissue diseases to PAH.
T28 9156-9279 Epistemic_statement denotes However, over time the right ventricle becomes thickened, enlarged and dysfunctional, which can culminate in heart failure.
T29 9530-9679 Epistemic_statement denotes It appears that upregulation of ACE2 and the subsequent increase in Ang-(1-7) levels may be a compensatory response to protect against tissue injury.
T30 9680-9830 Epistemic_statement denotes This view is supported by several experimental studies, wherein administration of ACE2 or Ang-(1-7) exerted cardio-protective effects [48] [49] [50] .
T31 10349-10483 Epistemic_statement denotes Part of the protective mechanism of ACE2 may be related to decrease in the levels of Ang II and/or the ensuing increase in Ang-(1-7) .
T32 10484-10650 Epistemic_statement denotes Besides this, modulation of matrix metalloproteinases (MMP) by ACE2, especially that of MMP-2 and MMP-9 may also be responsible for the anti-remodeling effects [52] .
T33 10746-10918 Epistemic_statement denotes Furthermore, ACE2 overexpression has been shown to inhibit hypoxia-induced collagen production by cardiac fibroblasts, highlighting the anti-fibrotic actions of ACE2 [54] .
T34 11298-11496 Epistemic_statement denotes In vitro studies have shown that decreased ACE2 level is associated with hyper-proliferation and enhanced migration of pulmonary smooth muscle cells, suggesting a vasoprotective role for ACE2 [56] .
T35 12369-12469 Epistemic_statement denotes A stoichiometric balance between NO and superoxide is critical for maintaining normal vascular tone.
T36 12667-12797 Epistemic_statement denotes On the other hand, ACE2 has been shown to reduce Ang II mediated superoxide production [60] , thereby improving vascular function.
T37 12955-13093 Epistemic_statement denotes In this regard, treatment with ACE2 or XNT has been shown to decrease the expression of pro-inflammatory cytokines in the lungs [6] [38] .
T38 13234-13376 Epistemic_statement denotes Taken together, experimental evidence indicates a protective role for ACE2 against endothelial dysfunction, oxidative stress and inflammation.
T39 13377-13522 Epistemic_statement denotes In light of the limited efficacy of currently available treatment options for PAH therapy, development of novel therapeutic strategies is needed.
T40 13523-13578 Epistemic_statement denotes In this regard, discovery of ACE2 seems to be relevant.
T41 13579-13915 Epistemic_statement denotes As discussed above, ACE2 has been shown to exert a host of beneficial effects on the cardio-pulmonary system, resulting in the prevention of PAH ( Figure 2) .Thus, it appears that genetic approaches to increase ACE2 activity and/or the use of synthetic ACE2 activators may represent potential new therapies for effectively treating PAH.