LitCovid-sentences  

PMC:7121452 / 4129-8985 JSONTXT 15 Projects

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Id Subject Object Predicate Lexical cue
T18 0-54 Sentence denotes Uncertain Effects of RAAS Inhibitors on ACE2 in Humans
T19 55-205 Sentence denotes Tissue-specific and circulating components of the RAAS make up a complex intersecting network of regulatory and counterregulatory peptides (Figure 1).
T20 206-380 Sentence denotes ACE2 is a key counterregulatory enzyme that degrades angiotensin II to angiotensin-(1–7), thereby attenuating its effects on vasoconstriction, sodium retention, and fibrosis.
T21 381-1030 Sentence denotes Although angiotensin II is the primary substrate of ACE2, that enzyme also cleaves angiotensin I to angiotensin-(1–9) and participates in the hydrolysis of other peptides.16 In studies in humans, tissue samples from 15 organs have shown that ACE2 is expressed broadly, including in the heart and kidneys, as well as on the principal target cells for SARS-CoV-2 (and the site of dominant injury), the lung alveolar epithelial cells.17 Of interest, the circulating levels of soluble ACE2 are low and the functional role of ACE2 in the lungs appears to be relatively minimal under normal conditions18 but may be up-regulated in certain clinical states.
T22 1031-1221 Sentence denotes Because ACE inhibitors and ARBs have different effects on angiotensin II, the primary substrate of ACE2, the effects of these agents on ACE2 levels and activity may be anticipated to differ.
T23 1222-1323 Sentence denotes Despite substantial structural homology between ACE and ACE2, their enzyme active sites are distinct.
T24 1324-1792 Sentence denotes As a result, ACE inhibitors in clinical use do not directly affect ACE2 activity.19 Experimental animal models have shown mixed findings with respect to the effects of ACE inhibitors on ACE2 levels or activity in tissue.20-25 Similarly, animal models have had inconsistent findings with respect to the effects of ARBs on ACE2, with some showing that ARBs may increase messenger RNA expression or protein levels of ACE2 in tissue21,26-34 and others showing no effect.23
T25 1793-1925 Sentence denotes In contrast to available animal models, there are few studies in humans regarding the effects of RAAS inhibition on ACE2 expression.
T26 1926-2645 Sentence denotes In one study, the intravenous administration of ACE inhibitors in patients with coronary artery disease did not influence angiotensin-(1–7) production, a finding that calls into question whether ACE inhibitors have any direct effects on ACE2-directed angiotensin II metabolism.35 Similarly, in another study, among patients with hypertension, angiotensin-(1–7) levels appeared to be unaffected after initial treatment with the ACE inhibitor captopril; however, with exposure to captopril monotherapy over a period of 6 months, angiotensin-(1–7) levels increased.36 Furthermore, few studies have examined plasma ACE2 activity or urinary ACE2 levels in patients who have received long-term treatment with RAAS inhibitors.
T27 2646-2907 Sentence denotes In cross-sectional studies involving patients with heart failure,37 atrial fibrillation,38 aortic stenosis,39 and coronary artery disease,40 plasma ACE2 activity was not higher among patients who were taking ACE inhibitors or ARBs than among untreated patients.
T28 2908-3542 Sentence denotes In a longitudinal cohort study involving Japanese patients with hypertension, urinary ACE2 levels were higher among patients who received long-term treatment with the ARB olmesartan than among untreated control patients, but that association was not observed with the ACE inhibitor enalapril or with other ARBs (losartan, candesartan, valsartan, and telmisartan).41 Previous treatment with ACE inhibitors was associated with increased intestinal messenger RNA levels of ACE2 in one study, but that association was not observed with ARBs25; data are lacking regarding the effects of RAAS inhibitors on lung-specific expression of ACE2.
T29 3543-3758 Sentence denotes These seemingly conflicting data indicate the complexity underlying RAAS responses to pathway modulators and reinforce the concept that findings from preclinical models may not readily translate to human physiology.
T30 3759-4309 Sentence denotes Such data do suggest that effects on ACE2 should not be assumed to be uniform across RAAS inhibitors or even in response to therapies within a given drug class.41 It is important to note that the plasma ACE2 level may not be a reliable indicator of the activity of the full-length membrane-bound form, in part because ACE2 is shed from the membrane, a process that appears to be separately regulated by an endogenous inhibitor.42 In addition to the degree of expression, the biologic relevance of ACE2 may vary according to tissue and clinical state.
T31 4310-4493 Sentence denotes Unfortunately, data showing the effects of ACE inhibitors, ARBs, and other RAAS inhibitors on lung-specific expression of ACE2 in experimental animal models and in humans are lacking.
T32 4494-4728 Sentence denotes Furthermore, even if RAAS inhibitors modify ACE2 levels or activity (or both) in target tissue beds, clinical data are lacking to indicate whether this would in turn facilitate greater engagement and entry of SARS-CoV-2 spike protein.
T33 4729-4856 Sentence denotes Further mechanistic studies in humans are needed to better define the unique interplay between SARS-CoV-2 and the RAAS network.