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CORD-19:2c8a8461d046eeda9f76e88e5db50af4af949e22 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T1 0-63 Sentence denotes ACE2, a Promising Therapeutic Target for Pulmonary Hypertension
T2 65-73 Sentence denotes Abstract
T3 74-190 Sentence denotes Pulmonary arterial hypertension (PAH) is a chronic lung disease with poor diagnosis and limited therapeutic options.
T4 191-301 Sentence denotes The current available therapies are ineffective in improving the quality of life and reducing mortality rates.
T5 302-466 Sentence denotes There exists a clear unmet medical need to treat this disease, which necessitates the discovery of novel therapeutic targets/agents for safe and successful therapy.
T6 467-578 Sentence denotes An altered renin-angiotensin system (RAS) has been implicated as a causative factor in the pathogenesis of PAH.
T7 579-795 Sentence 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.
T8 796-886 Sentence denotes Recently, a new member of the RAS, Angiotensin converting enzyme 2 (ACE2), was discovered.
T9 887-1042 Sentence denotes This enzyme functions as a negative regulator of the angiotensin system by metabolizing Angiotensin II to a putative protective peptide, Angiotensin-(1-7).
T10 1043-1178 Sentence denotes ACE2 is abundantly expressed in the lung tissue and emerging evidence suggests a beneficial role for this enzyme against lung diseases.
T11 1179-1313 Sentence denotes In this review, we focus on ACE2 in relation to pulmonary hypertension and provide proof of principle for its therapeutic role in PAH.
T12 1315-1485 Sentence denotes Pulmonary arterial hypertension (PAH) is a debilitating chronic disorder of the lungs characterized by sustained elevation of blood pressure in the pulmonary vasculature.
T13 1486-1574 Sentence denotes The normal mean pulmonary arterial pressure in a healthy adult is about 14mm Hg at rest.
T14 1575-1707 Sentence denotes However, in PAH, the resting mean pulmonary arterial pressure measures over 25mm Hg (and greater than 30mm Hg during exercise) [1] .
T15 1708-1897 Sentence 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.
T16 1898-1981 Sentence denotes Genetic and epigenetic risk factors have also been linked to PAH pathogenesis [2] .
T17 1982-2112 Sentence denotes Regardless of the cause, PAH is associated with endothelial dysfunction, vasoconstriction and remodeling of the pulmonary vessels.
T18 2113-2363 Sentence 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•].
T19 2364-2635 Sentence denotes This imbalance leads to a cascade of events resulting in hyper-proliferation of pulmonary smooth muscle cells, activation of lung fibroblasts, induction of thrombotic mediators and release of inflammatory cytokines, all of which increase vascular resistance and pressure.
T20 2636-2757 Sentence denotes One of the causal factors for endothelial dysfunction and vascular impairment is the renin-angiotensin system (RAS) [4] .
T21 2758-2997 Sentence denotes Activation of the classic ACE-AngII-AT1R axis of the RAS, comprising of Angiotensin converting enzyme (ACE), the vasoactive peptide Angiotensin II (Ang II), and its receptor AT1R, adversely affects pulmonary hemodynamics to cause PAH [5] .
T22 2998-3170 Sentence 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••].
T23 3171-3392 Sentence 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.
T24 3393-3508 Sentence denotes The RAS is composed of a series of enzymatic reactions that lead to the generation of several angiotensin peptides.
T25 3509-3632 Sentence denotes The cascade begins with the proteolytic cleavage of angiotensinogen by renin to yield the inactive precursor Angiotensin I.
T26 3633-3851 Sentence denotes Angiotensin I is further acted upon by Angiotensin converting enzyme (ACE) to form Angiotensin II (Ang II), a biologically active vasopeptide that mediates its effects via two distinct receptor subtypes -AT1R and AT2R.
T27 3852-4005 Sentence denotes Stimulation of the AT1R causes vasoconstriction, cell proliferation, inflammation and fibrosis, while activation of AT2R regulates opposing effects [7] .
T28 4006-4131 Sentence denotes Several new members of the RAS have recently been identified, which has expanded our understanding of this biological system.
T29 4132-4278 Sentence 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] .
T30 4279-4430 Sentence denotes All the major components of the RAS including Renin, Angiotensinogen, ACE, ACE2, AT1R, AT2R and the Mas receptor are expressed in the lung tissue [5] .
T31 4431-4583 Sentence 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.
T32 4584-4804 Sentence denotes With regard to the ACE gene, an insertion-deletion polymorphism of 287 base pairs in intron 16 results in 3 distinct genotypes; DD(homozygous deletion allele), II( homozygous insertion allele) and ID heterozygotes [16] .
T33 4805-4953 Sentence denotes The deletion allele (DD) is associated with increased ACE activity, while the insertion allele (II) is associated with decreased ACE activity [17] .
T34 4954-5081 Sentence denotes The ACE DD genotype, accompanied by elevated circulating levels of Ang II, has been implicated in the development of PAH [18] .
T35 5082-5272 Sentence 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] .
T36 5273-5346 Sentence denotes ACE is the primary enzyme responsible for Ang II production in the lungs.
T37 5347-5434 Sentence denotes This Ang II peptide is a potent pulmonary vasoconstrictor with mitogenic actions [20] .
T38 5435-5610 Sentence denotes Both animal and clinical studies have shown that stimulation of the pulmonary smooth muscle cells with Ang II produces migratory, hypertrophic and proliferative effects [21] .
T39 5611-5783 Sentence denotes Furthermore, Ang II initiates inflammatory processes and generates cellular reactive oxygen species (ROS), factors that contribute to the pathophysiology of PAH [22] [23] .
T40 5784-5921 Sentence denotes Accumulating evidence also suggests that Ang II induces apoptosis of the lung parenchymal cells, leading to pulmonary hypertension [24] .
T41 5922-6029 Sentence denotes Collectively, these findings clearly indicate an active role for RAS in the pulmonary hypertensive process.
T42 6030-6212 Sentence 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.
T43 6213-6553 Sentence 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.
T44 6554-6697 Sentence denotes ACE2 was discovered as a close homologue of ACE about a decade ago, by two independent research groups using distinct methodologies [10] [11] .
T45 6698-6787 Sentence denotes It contains 805 amino acids and shares 42% sequence homology with the active site of ACE.
T46 6788-6945 Sentence 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.
T47 6946-7060 Sentence denotes Ang II appears to be the main substrate for ACE2, and is effectively hydrolyzed to Angiotensin-(1-7) [Ang-(1-7) ].
T48 7061-7218 Sentence denotes Apelin-13, Apelin 36, Neurotensin 1-8, Dynorphin A (1-13), [des-Arg9]-Bradykinin, and [Lys-des-Arg9]-Bradykinin are the other known peptide targets for ACE2.
T49 7219-7354 Sentence denotes ACE2 exists as a membrane-bound protein in the lungs, stomach, spleen, intestine, bone-marrow, kidney, liver, and the brain [33] [34] .
T50 7355-7561 Sentence denotes Particularly, in the lungs, it is expressed on the vascular endothelium, type I and type II alveolar epithelial cells, the smooth muscle cells of the pulmonary vasculature, and in bronchial epithelia [35] .
T51 7562-7685 Sentence denotes Though, ACE2 exists primarily as a membrane-bound protein, a soluble form has been detected in both plasma and urine [36] .
T52 7686-7760 Sentence denotes ACE2 has been suggested to play an important role in lung pathophysiology.
T53 7761-7817 Sentence denotes Evidence for this comes from the following observations:
T54 7818-8556 Sentence denotes 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.
T55 8557-8559 Sentence denotes A.
T56 8560-8630 Sentence denotes Johnson et al., abstract in Am J Respir Crit Care Med 181;2010:A6327).
T57 8631-8779 Sentence 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.
T58 8780-8863 Sentence denotes All these observations substantiate the importance of ACE2 in lung pathophysiology.
T59 8864-9008 Sentence denotes Remodeling of the right ventricle, characterized by myocyte hypertrophy and fibrosis is often observed in pulmonary hypertensive patients [45] .
T60 9009-9155 Sentence denotes During the early stages of PAH, the remodeling process represents an adaptive response to compensate for the increased right ventricular workload.
T61 9156-9279 Sentence denotes However, over time the right ventricle becomes thickened, enlarged and dysfunctional, which can culminate in heart failure.
T62 9280-9372 Sentence denotes In fact, right ventricular failure is the primary cause of death in patients with PAH [46] .
T63 9373-9529 Sentence denotes Zisman et al., were the first investigators to report increased ACE2 activity and elevated Angiotensin-(1-7) levels in the ventricles of PAH patients [47] .
T64 9530-9679 Sentence 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.
T65 9680-9830 Sentence denotes This view is supported by several experimental studies, wherein administration of ACE2 or Ang-(1-7) exerted cardio-protective effects [48] [49] [50] .
T66 9831-9947 Sentence denotes Conversely, ACE2 deficiency resulted in increased incidence of cardiac death due to chronic pressure overload [51] .
T67 9948-10147 Sentence denotes Of particular relevance to pulmonary therapeutics is that lung overexpression of ACE2 prevented the development of right ventricular hypertrophy in animal models of PAH and lung fibrosis (Figure 1 ).
T68 10148-10348 Sentence denotes Similar beneficial effects were also observed with endogenous activation of ACE2 using XNT (1-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one) [6].
T69 10349-10483 Sentence 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) .
T70 10484-10650 Sentence 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] .
T71 10651-10745 Sentence denotes It is well known that matrix metalloproteinases contribute to cardiac remodeling in PAH [53] .
T72 10746-10918 Sentence denotes Furthermore, ACE2 overexpression has been shown to inhibit hypoxia-induced collagen production by cardiac fibroblasts, highlighting the anti-fibrotic actions of ACE2 [54] .
T73 10919-11022 Sentence denotes All the layers of the pulmonary vessel wall undergo structural and functional changes during PAH [55] .
T74 11023-11190 Sentence denotes These changes include proliferation of the vascular smooth muscle cells, intimal thickening and extension of smooth muscle into previously non-muscularized arterioles.
T75 11191-11297 Sentence denotes Vascular remodeling reduces lumen diameter, thereby increasing pulmonary vascular resistance and pressure.
T76 11298-11496 Sentence 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] .
T77 11497-11710 Sentence denotes These in vitro data were further confirmed by in vivo studies, wherein lung overexpression of ACE2 not only prevented vessel wall thickening but also attenuated muscularization of the pulmonary vessels [38] [39] .
T78 11711-11870 Sentence denotes Administration of XNT, the synthetic ACE2 activator, also exerted similar beneficial effects on the pulmonary vasculature in an experimental model of PAH [6] .
T79 11871-12014 Sentence denotes Reduced bioavailability of nitric oxide (NO), increased formation of reactive oxygen species (ROS) and inflammation are hallmarks of PAH [57] .
T80 12015-12115 Sentence denotes Improvement of the aforementioned factors is essential for effective pulmonary hypertensive therapy.
T81 12116-12214 Sentence denotes ACE2 is predominantly localized to the vascular endothelium and exerts vasodilatory actions [58] .
T82 12215-12368 Sentence denotes On the contrary, deficiency in ACE2 impairs endothelium-dependent vasorelaxation [59] , which underscores the importance of ACE2 in endothelial function.
T83 12369-12469 Sentence denotes A stoichiometric balance between NO and superoxide is critical for maintaining normal vascular tone.
T84 12470-12666 Sentence denotes It is well established that Ang II increases superoxide production by upregulating endothelial nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) resulting in vascular impairment.
T85 12667-12797 Sentence denotes On the other hand, ACE2 has been shown to reduce Ang II mediated superoxide production [60] , thereby improving vascular function.
T86 12798-12954 Sentence denotes Inflammatory cytokines (e.g., IL-1, IL-6, TNF-α and MCP-1) and growth factors (TGF-β) substantially contribute to the development and/or progression of PAH.
T87 12955-13093 Sentence 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] .
T88 13094-13233 Sentence denotes Also, this decrease in pro-inflammatory cytokine levels was accompanied by a concomitant increase in the anti-inflammatory cytokine, IL-10.
T89 13234-13376 Sentence denotes Taken together, experimental evidence indicates a protective role for ACE2 against endothelial dysfunction, oxidative stress and inflammation.
T90 13377-13522 Sentence denotes In light of the limited efficacy of currently available treatment options for PAH therapy, development of novel therapeutic strategies is needed.
T91 13523-13578 Sentence denotes In this regard, discovery of ACE2 seems to be relevant.
T92 13579-13915 Sentence 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.
T93 13916-14160 Sentence denotes ACE2 exerts a host of actions on the cardio-pulmonary system that include prevention of endothelial dysfunction, reduction in pulmonary oxidative stress, attenuation of vascular impairment, anti-inflammatory and anti-cardiac remodeling effects.
T94 14161-14269 Sentence denotes All these properties are responsible for the protective role of ACE2 against pulmonary arterial hypertension