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Id Subject Object Predicate Lexical cue
T1 0-77 Sentence denotes Clinical Implications of SARS-CoV-2 Interaction With Renin Angiotensin System
T2 78-107 Sentence denotes JACC Review Topic of the Week
T3 109-117 Sentence denotes Abstract
T4 118-264 Sentence denotes Severe acute respiratory-syndrome coronavirus-2 (SARS-CoV-2) host cell infection is mediated by binding to angiotensin-converting enzyme 2 (ACE2).
T5 265-467 Sentence denotes Systemic dysregulation observed in SARS-CoV was previously postulated to be due to ACE2/angiotensin 1-7 (Ang1-7)/Mas axis downregulation; increased ACE2 activity was shown to mediate disease protection.
T6 468-772 Sentence denotes Because angiotensin II receptor blockers, ACE inhibitors, and mineralocorticoid receptor antagonists increase ACE2 receptor expression, it has been tacitly believed that the use of these agents may facilitate viral disease; thus, they should not be used in high-risk patients with cardiovascular disease.
T7 773-1130 Sentence denotes Based on the anti-inflammatory benefits of the upregulation of the ACE2/Ang1-7/Mas axis and previously demonstrated benefits of lung function improvement in SARS-CoV infections, it has been hypothesized that the benefits of treatment with renin-angiotensin system inhibitors in SARS-CoV-2 may outweigh the risks and at the very least should not be withheld.
T8 1132-1152 Sentence denotes Central Illustration
T9 1154-1164 Sentence denotes Highlights
T10 1165-1222 Sentence denotes • COVID-19 has been associated with cardiac involvement.
T11 1223-1270 Sentence denotes SARS-CoV-2 requires binding to ACE2 in the RAS.
T12 1271-1385 Sentence denotes • The ACE2/Ang1-7/Mas pathway counterbalances the RAS, which results in activation of anti-inflammatory pathways.
T13 1386-1460 Sentence denotes • ACE inhibitors, ARBs, and MRAs upregulate ACE2 activity and expression.
T14 1461-1612 Sentence denotes • More data are required to determine if regulation of ACE2 in patients with cardiovascular disease and COVID-19 would help improve clinical outcomes.
T15 1614-1903 Sentence denotes The novel coronavirus disease-2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), originated from the Wuhan, Hubei providence in central China in December 2019 and was declared a pandemic by the World Health Organization on March 11, 2020 (1).
T16 1904-2027 Sentence denotes Compared with SARS-CoV, which caused the 2002 to 2003 outbreak, SARS-CoV-2 appears to have a stronger rate of transmission.
T17 2028-2201 Sentence denotes Although the SARS infection exhibits a prolonged clinical course predominantly involving respiratory manifestations, the clinical course of the novel coronavirus is unclear.
T18 2202-2415 Sentence denotes Further clinical insights from Wuhan suggest that some patients with COVID-19 exhibit severe cardiovascular damage, and those with underlying cardiovascular disease appear to have an increased risk of death (1,2).
T19 2416-2484 Sentence denotes Both SARS-CoV and CoV2 belong to the beta-coronavirus phylogeny (3).
T20 2485-2676 Sentence denotes Although bats may be natural reservoirs for SARS-like coronavirus (3), interspecies transfer of SARS-CoV and SARS-CoV-2 could have occurred through civets (4) and pangolins (5), respectively.
T21 2677-2831 Sentence denotes Both SARS-CoV strains have been identified to use the angiotensin-converting enzyme 2 (ACE2) receptor as the portal of entry into the affected cell (1,4).
T22 2832-3059 Sentence denotes ACE2 is a key modulator of the renin-angiotensin system (RAS), which is a signaling pathway involved in the regulation of vascular function, including the regulation of blood pressure, natriuresis, and blood volume control (6).
T23 3060-3365 Sentence denotes Normally, the RAS involves the formation of angiotensin II (Ang II) through ACE, which contributes to multiple cardiovascular physiological and pathophysiological functions, including hypertension, myocardial hypertrophy, cardiac fibrosis, inflammation, vascular remodeling, and atherosclerosis (7, 8, 9).
T24 3366-3635 Sentence denotes Because of the adverse cardiovascular effects of RAS upregulation, its inhibition through ACE inhibitors, angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) has been critical for the management of various cardiovascular diseases.
T25 3636-3813 Sentence denotes In the last 2 decades, the identification of ACE2 and its involvement in the counter regulation of the classic RAS has offered a potentially new therapeutic target (10, 11, 12).
T26 3814-3948 Sentence denotes ACE2 exists both as membrane-bound and soluble forms, the former of which mediates SARS-CoV-2 infection via S-protein binding (13,14).
T27 3949-4104 Sentence denotes It is unclear whether SARS-CoV-2 interferes with ACE2 in a manner that contributes to the pathogenesis of SARS or the cardiovascular damage observed (1,2).
T28 4105-4245 Sentence denotes This raises the question of whether RAS inhibition in cardiovascular patients should be reassessed in the setting of this novel coronavirus.
T29 4247-4278 Sentence denotes Angiotensin-Converting Enzyme 2
T30 4279-4379 Sentence denotes Classically, the RAS involves the conversion of angiotensinogen by renin into angiotensin I (Ang I).
T31 4380-4450 Sentence denotes Ang I is metabolized to Ang II via the dipeptide carboxypeptidase ACE.
T32 4451-4551 Sentence denotes The pro-inflammatory effects of Ang II (7, 8, 9) are mediated through Ang II type I (AT1) receptors.
T33 4552-4686 Sentence denotes Recently, the ACE2 receptor and its signaling pathway were identified as an important counter regulatory mechanism to the classic RAS.
T34 4687-4862 Sentence denotes ACE2 is a type I integral membrane glycoprotein (15) expressed predominantly in the bronchus, lung parenchyma, heart, endothelium, kidneys, duodenum, and small intestine (16).
T35 4863-4991 Sentence denotes ACE2 is a monocarboxypeptidase, unlike its homolog, ACE, which is a dipeptidase; ACE2 is not antagonized by ACE inhibitors (17).
T36 4992-5113 Sentence denotes Although ACE contains 2 active catalytic domains, ACE2 has a single catalytic domain with 42% identical residues (18,19).
T37 5114-5244 Sentence denotes The major substrate of ACE2 is Ang II, which upon C-terminus cleavage, produces angiotensin 1-7 (Ang1-7) and L-phenylalanine (20).
T38 5245-5365 Sentence denotes Other substrates for ACE2 include Ang I, apelin-13, and dynorphin-13, which are catalyzed at much lower affinities (21).
T39 5366-5554 Sentence denotes The non-catalytic C-terminal domain of ACE2 shares a 48% sequence homology with collectrin, a protein involved in neutral amino acid reabsorption from the intestine and the kidney (22,23).
T40 5555-5784 Sentence denotes In the presence of a disintegrin and metalloproteinase 17 (ADAM17), also known as tumor necrosis factor (TNF)-α−converting enzyme (TACE), ACE2 exhibits ectodomain shedding (24), which results in the formation of a soluble enzyme.
T41 5785-5889 Sentence denotes ACE2 also contains a calmodulin domain on its cytoplasmic tail that influences ectodomain shedding (25).
T42 5891-5922 Sentence denotes ACE2/Ang1-7/Mas Axis Regulation
T43 5923-5999 Sentence denotes Ang I is a decapeptide that is converted into the octapeptide Ang II by ACE.
T44 6000-6126 Sentence denotes Unlike ACE, Ang I can be converted to Ang1-9 by ACE2, and, more importantly, Ang II is converted to Ang 1-7 through ACE2 (17).
T45 6127-6302 Sentence denotes Ang1-7 has a range of anti-inflammatory, antioxidant, vasodilatory, and natriuretic effects that are mediated by the G protein coupled receptor (GPCR) Mas receptor (11,26,27).
T46 6303-6517 Sentence denotes Ang1-7 may be produced directly from Ang I through the alternative pathways involving a zinc metallopeptidase neprilysin or conversion of Ang1-9 to Ang1-7 via ACE, although at a significantly lower efficiency (17).
T47 6518-6623 Sentence denotes Genetic deletion studies have established ACE2 as an essential regulator of cardiovascular function (28).
T48 6624-6884 Sentence denotes Studies focused on the regulation of ACE2 in cardiac myocytes and cardiac fibroblasts have demonstrated that although Ang II significantly reduced ACE2 activity and downregulated ACE2 mRNA in cardiac myocytes, it only reduced ACE2 activity in fibroblasts (29).
T49 6885-6971 Sentence denotes In myocytes, endothelin (ET)-1 also significantly decreased ACE2 mRNA production (29).
T50 6972-7207 Sentence denotes This reduction in ACE2 mRNA by Ang II or ET-1 was blocked by inhibitors of mitogen-activated protein kinase 1 (MAPK1), which suggested that Ang II and ET-1 activate extracellular signal-regulated kinase (ERK)1/ERK2 to reduce ACE2 (29).
T51 7208-7419 Sentence denotes Furthermore, in vivo murine studies showed Ang II−mediated loss of membrane-bound cardiomyocyte ACE2 correlated with the upregulation of TACE/ADAM17 activity, which was prevented with AT1 receptor blockade (30).
T52 7420-7576 Sentence denotes Cardiac fibroblasts and coronary endothelial cells also express ACE2 and TACE, and this reciprocal relationship extends to these cell types as well (31,32).
T53 7577-7747 Sentence denotes Ang II activates several other signaling cascades, such as the PKC and JAK2-STAT3 signaling pathways, which results in myocardial hypertrophy and increased fibrosis (33).
T54 7748-7890 Sentence denotes The binding of Ang1-7 to the C-terminal domain also inhibits the proteolytic function of the ACE enzyme and promotes bradykinin function (34).
T55 7891-8103 Sentence denotes Studies in human vascular and cardiac tissue and plasma showed Ang1-7 has a higher affinity to ACE than Ang I, which suggests the inhibitory effects of Ang1-7 on ACE may contribute to its protective effects (35).
T56 8104-8405 Sentence denotes The treatment of ACE2 knockout mice with Ang II infusion and recombinant ACE2 (rhACE2) eliminated ERK1/2, JAK2-STAT3, and PKC signaling by rhACE2 and was at least partially responsible for attenuation of Ang II−induced myocardial hypertrophy and fibrosis and improvement in diastolic dysfunction (33).
T57 8406-8758 Sentence denotes Other studies highlighted the role of the ACE2/Ang1-7/Mas axis in modulating the expression of pro-inflammatory cytokines, such as TNF-α, interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1, and transforming growth factor-β in cardiac and/or lung fibrosis, pulmonary hypertension, and vascular remodeling (36, 37, 38, 39, 40, 41) (Figure 1 ).
T58 8759-8807 Sentence denotes Figure 1 RAS and ACE2/Ang1-7/Mas Axis Regulation
T59 8808-8872 Sentence denotes Angiotensinogen is converted to angiotensin I (Ang I) via renin.
T60 8873-9030 Sentence denotes Ang I is converted to Ang II via angiotensin-converting enzyme (ACE), which also hydrolyzes bradykinin into its inactive metabolites, promoting inflammation.
T61 9031-9234 Sentence denotes The pro-inflammatory effects of Ang II are mediated by Ang II type I receptor (AT1), which stimulates aldosterone secretion from the adrenal medulla and antidiuretic hormone from the posterior pituitary.
T62 9235-9282 Sentence denotes Aldosterone decreases membrane ACE2 expression.
T63 9283-9393 Sentence denotes Endothelin-1 inhibits angiotensin 1-7 (Ang1-7) via extracellular signal-regulated kinase (ERK)1/ERK2 pathways.
T64 9394-9547 Sentence denotes Ang II, under favorable conditions (dashed line), can be converted to Ang1-7 via ACE2, whose counter regulatory effects are mediated by the Mas receptor.
T65 9548-9700 Sentence denotes Ang1-7 can also be formed via conversion of Ang I to an intermediate Ang1-9 or directly via zinc metallopeptidase neprilysin/prolyl endopeptidase (PEP).
T66 9701-9732 Sentence denotes RAS = renin-angiotensin system.
T67 9734-9776 Sentence denotes ACE2 Regulation and Cardiovascular Disease
T68 9777-9989 Sentence denotes Because of the importance of the RAS in cardiovascular disease, its regulation via ACE inhibitors, ARBs, and MRAs has played an essential role in the management of cardiovascular diseases (Central Illustration ).
T69 9990-10065 Sentence denotes Central Illustration The Renin-Angiotensin System Interaction With COVID-19
T70 10066-10205 Sentence denotes Normally, angiotensin I (Ang I) is converted to Ang II via angiotensin-converting enzyme (ACE), which could be inhibited by ACE inhibitors.
T71 10206-10287 Sentence denotes The pro-inflammatory effects of Ang II are mediated through AT1R in several ways:
T72 10288-10773 Sentence denotes 1) in the zona glomerulosa of the adrenal medulla, it stimulates aldosterone secretion and binding to mineralocorticoid receptors to promote water reabsorption and to increase salt retention; it is inhibited by mineralocorticoid receptor antagonists (MRAs); 2) in the posterior pituitary, Ang II stimulates antidiuretic hormone secretion to promote water retention; and 3) in other tissues, it stimulates pathways responsible for hypertrophy, fibrosis, oxidative stress, and apoptosis.
T73 10774-10879 Sentence denotes These effects are attenuated by angiotensin receptor blockers (ARBs), which block Ang II binding to AT1R.
T74 10880-11019 Sentence denotes Ang II can also be converted to angiotensin 1-7 (Ang 1-7) via ACE2, which stimulates the Mas receptor promoting anti-inflammatory benefits.
T75 11020-11132 Sentence denotes The ACE2/Ang1-7/Mas axis acts as a counter regulatory pathway to the traditional renin-angiotensin system (RAS).
T76 11133-11159 Sentence denotes AT1R and ACE2 are coupled.
T77 11160-11238 Sentence denotes Ang II binding to AT1R allows dissociation of ACE2 and subsequent degradation.
T78 11239-11341 Sentence denotes ARB prevents dissociation of ACE2 and renders it availability for unused Ang II conversion to Ang 1-7.
T79 11342-11477 Sentence denotes ACE2 has been identified as the targeted receptor for both the severe acute respiratory syndrome coronavirus (SARS-CoV) 2 and SARS-CoV.
T80 11478-11608 Sentence denotes ACE2 mediates S protein binding that stimulates viral entry into the host cytosol that results in infection and viral replication.
T81 11609-11799 Sentence denotes Diversion of Ang II towards ACE2 could competitively inhibit viral binding and also counter regulate the adverse effects caused by AT1R and improve outcomes by Mas R−based favorable effects.
T82 11800-11909 Sentence denotes Several studies have elucidated the role of these drug classes on the modulation of the ACE2/Ang1-7/Mas axis.
T83 11910-12075 Sentence denotes Mouse peritoneal macrophages treated in vitro with aldosterone, demonstrated significantly increased ACE activity as well as ACE mRNA and significantly reduced ACE2.
T84 12076-12358 Sentence denotes However, in mouse peritoneal macrophages treated with nicotinamide adenine dinucleotide phosphate oxidase inhibitor, aldosterone could not increase ACE or decrease ACE2, which suggested these effects were mediated in part by nicotinamide adenine dinucleotide phosphate oxidase (42).
T85 12359-12439 Sentence denotes These effects were also attenuated with treatment with an MRA (eplerenone) (42).
T86 12440-12678 Sentence denotes Human monocyte-derived macrophages obtained from patients with heart failure before and after 1 month of treatment with another MRA (spironolactone; 25 mg/day) showed 47% reduction in ACE activity and 53% reduction in ACE mRNA expression.
T87 12679-12777 Sentence denotes At the same time, ACE2 activity increased by 300% and ACE2 mRNA expression increased by 654% (42).
T88 12778-12928 Sentence denotes In mice treated for 2 weeks with eplerenone, cardiac ACE2 activity increased 2-fold and was paralleled by increased ACE2 activity in macrophages (42).
T89 12929-13175 Sentence denotes This study demonstrated that the MRA reduced oxidative stress, decreased ACE activity, and increased ACE2 activity and/or expression, which suggested the protective role played by increased generation of Ang 1-7 and decreased formation of Ang II.
T90 13176-13504 Sentence denotes Overall, aldosterone decreased ACE2 transcription through a nicotinamide adenine dinucleotide phosphate oxidase−mediated pathway (42), and in vascular smooth muscle cells, potentiated Ang II signaling with increased phosphorylation of ERK1/2 and c-Jun kinase, which are also dependent on reactive oxygen species generation (43).
T91 13505-13649 Sentence denotes Thus, the beneficial effects of MRAs are likely associated with reduction of oxidative stress and differential control of these angiotensinases.
T92 13650-13807 Sentence denotes MRAs appeared to promote membrane ACE2 expression and suppress the peripheral effects of Ang II; however, the effect of MRAs on soluble ACE2 remains unclear.
T93 13808-13901 Sentence denotes Similar upregulation of ACE2 was observed in studies focused on the effects of ARB treatment.
T94 13902-14165 Sentence denotes Spontaneously hypertensive rats treated with olmesartan demonstrated a 5-fold greater expression of ACE2 mRNA and increased Ang1-7 in their thoracic aortas, whereas those treated with atenolol and hydralazine exhibited no change in ACE2 expression or Ang1-7 (44).
T95 14166-14400 Sentence denotes Comparison of vessel wall dimensions showed that olmesartan selectively reduced the thoracic aorta media-to-lumen ratio, whereas vascular hypertrophy was unchanged in spontaneously hypertensive rats given atenolol or hydralazine (44).
T96 14401-14510 Sentence denotes There was no change in ACE2/Ang1-7 expression and/or activity in the carotid arteries of the treated animals.
T97 14511-14761 Sentence denotes The possibility that the effects of olmesartan on vascular ACE2 gene and protein expression were the result of reduced arterial blood pressure was ruled out because of the comparative effect observed in mice treated with atenolol or hydralazine (44).
T98 14762-15019 Sentence denotes Sprague-Dawley rats treated with a 4-week course of Ang II infusion showed Ang II upregulated AT1 receptor, downregulated AT2 receptor, ACE2 activity, endothelial nitric oxide synthase expression, as well as increased CD44 expression and hyaluronidase (45).
T99 15020-15263 Sentence denotes However, rats treated with telmisartan exhibited significantly increased ACE2 activity and endothelial nitric oxide synthase expression in intracardiac vessels and intermyocardium, as well as downregulated local expression of the AT1 receptor.
T100 15264-15397 Sentence denotes Treatment with telmisartan also inhibited membrane CD44 expression and reduced transforming growth factor−β and Smad expression (45).
T101 15398-15643 Sentence denotes Studies in normotensive rats with post-coronary artery ligation left ventricular remodeling and dysfunction exhibited partial resolution following losartan and olmesartan treatment while augmenting plasma concentrations of the angiotensins (46).
T102 15644-15930 Sentence denotes This was associated with recovery of cardiac AT1 receptor mRNA and increased ACE2 mRNA post-myocardial infarction, which implied the beneficial effects of ARBs on cardiac remodeling were accompanied by direct blockade of AT1 receptors and increased ACE2 expression and/or activity (46).
T103 15931-16153 Sentence denotes The literature offers conflicting results pertaining to ARB use and the level of ACE2 expression on the myocardium; most of the controversy arises from the difference in ACE2 cell surface expression and plasma ACE2 levels.
T104 16154-16399 Sentence denotes In the Sprague-Dawley rats with left coronary artery ligation and myocardial infarction, plasma Ang II and Ang1-7 were not elevated, but plasma ACE2 was elevated, along with enhanced cardiac ACE2 and AT1 receptor mRNA at the infarct border (47).
T105 16400-16469 Sentence denotes Receptor upregulation was not observed in the remote myocardium (47).
T106 16470-16784 Sentence denotes Treatment with ramipril and valsartan resulted in increased plasma Ang I and Ang II and suppression in plasma ACE and ACE2 activity; however, neither monotherapy nor combination therapy affected ACE2 or AT1 receptor expression, both of which remained at levels comparable to non-myocardial infarction control (47).
T107 16785-16952 Sentence denotes However, a previous study in the same murine model showed ACE and ACE2 upregulation in the border, infarct zones, and in viable myocardium after myocardial infarction.
T108 16953-17084 Sentence denotes Treatment with ramipril reduced ACE expression, whereas ACE2 remained elevated compared with the noninfarcted control subject (48).
T109 17085-17371 Sentence denotes A recent study in the same murine model demonstrated that treatment with olmesartan or telmisartan increased both cardiac ACE2 mRNA and protein expression while augmenting plasma Ang1-7/Ang II ratios, which resulted in improved cardiac function and alleviated collagen disposition (49).
T110 17372-17476 Sentence denotes These experiments suggested that both ACE inhibitors and ARBs variably upregulated ACE2 expression (49).
T111 17477-17613 Sentence denotes ARBs inhibited binding of Ang II to the AT1 receptor, which permitted circulating Ang II to be shunted to ACE2 for conversion to Ang1-7.
T112 17614-17804 Sentence denotes These studies suggest that the ACE2/Ang1-7 axis collaborates with or is regulated by the AT1 receptor and may be important in mediating the vascular and cardiac remodeling effects of Ang II.
T113 17805-17860 Sentence denotes The mechanisms by which ACE inhibitors act are complex.
T114 17861-18013 Sentence denotes Although ACE2 is not inhibited by ACE inhibitors (19), an increase in Ang1-7 suggests their clinical effects are partly mediated by the angiotensinases.
T115 18014-18112 Sentence denotes ACE inhibitors inhibit the conversion of Ang I to Ang II and inhibit the hydrolysis of bradykinin.
T116 18113-18335 Sentence denotes ACE inhibition promotes the vasodilatory effects of bradykinin, improved endothelium-dependent vasodilation through increased prostaglandin and nitric oxide production, and down regulation of the AT1 receptor (50, 51, 52).
T117 18336-18496 Sentence denotes Studies that elucidated the effect of ACE inhibition on the ACE2 gene showed that inhibition of Ang II synthesis regulated ACE2 mRNA but not ACE2 activity (53).
T118 18497-18636 Sentence denotes However, ACE inhibition alone or in combination with losartan was demonstrated to increase plasma Ang1-7 while reducing plasma Ang II (53).
T119 18637-18908 Sentence denotes Compared with the degree of ACE2 mRNA upregulation seen with post-losartan monotherapy, combination of losartan and lisinopril resulted in suppressed upregulation of ACE2 mRNA, which suggested ACE inhibitors might override a signal that regulates ACE2 transcription (53).
T120 18909-19190 Sentence denotes Although Ang II is the predominant substrate, ACE2 can also convert Ang I into Ang 1-9, which, in turn, could be converted to Ang 1-7 via ACE; Ang I can be directly converted into Ang 1-7 via zinc metallopeptidase neprilysin (17), although with less favorable kinetics at baseline.
T121 19191-19353 Sentence denotes Thus, it can be assumed ACE inhibitors disrupt the balance between catalytically active ACE and ACE2, resulting in favored activation of the ACE2/Ang1-7/Mas axis.
T122 19354-19551 Sentence denotes Overall, because of the demonstrated anti-inflammatory, antifibrotic, and antithrombotic effects associated with the ACE2/Ang1-7/Mas axis, upregulation could serve as a valuable therapeutic target.
T123 19553-19569 Sentence denotes ACE2 and Ang1-7:
T124 19570-19585 Sentence denotes Clinical Trials
T125 19586-19721 Sentence denotes ACE2 regulates RAS signaling by reducing Ang II/AT1 receptor signaling and by activating the ACE2/Ang1-7/Mas counterregulatory pathway.
T126 19722-19890 Sentence denotes Thus far, only a few pilot clinical studies have been conducted using rhACE2 in acute respiratory distress syndrome (ARDS), sepsis, and pulmonary arterial hypertension.
T127 19891-20022 Sentence denotes Multiple murine studies demonstrated rhACE2 modulates the RAS pathway, although it is unclear if these effects translate to humans.
T128 20023-20400 Sentence denotes A clinical study (Safety and Tolerability Study of APN01 [Recombinant Human Angiotensin Converting Enzyme 2]; NCT00886353) that assessed the pharmacokinetics and pharmacodynamics of soluble rhACE2 treatment in healthy volunteers with no known comorbidities showed a decrease in plasma Ang1-8 and increased Ang1-7 and Ang1-5 with no effect on blood pressure and heart rate (54).
T129 20401-20452 Sentence denotes Common side effects included diarrhea and headache.
T130 20453-20574 Sentence denotes No antibodies to rhACE2 developed, which suggested there was no elicit immune response to single or repeated dosing (54).
T131 20575-20646 Sentence denotes Further studies investigating the immunogenicity of rhACE are required.
T132 20647-20732 Sentence denotes Serum levels of ACE and Ang II are elevated in patients with ARDS and sepsis (55,56).
T133 20733-21137 Sentence denotes Studies focused on microvascular dysfunction in sepsis showed that the degree of elevation in plasma renin and Ang II were correlated with the extent of organ failure and the degree of microvascular dysfunction, especially in patients who received exogenous vasoconstrictors (56); there was also a negative correlation between re-oxygenation rates and both concentrations of plasma renin and Ang II (56).
T134 21138-21439 Sentence denotes In a pilot clinical trial (Safety, Tolerability, PK and PD of GSK2586881 in Patients With Acute Lung Injury; NCT01597635), patients with ARDS who were treated with rhACE2 exhibited decreased plasma Ang II and elevated plasma Ang 1-7 and surfactant protein-D, which is involved in innate immunity (57).
T135 21440-21602 Sentence denotes IL-6 concentrations in treated patients were also reduced, albeit statistically insignificantly, which was due to intrasubject variability and baseline imbalance.
T136 21603-21763 Sentence denotes Although rhACE2 attenuated RAS mediators, infusions of the medication did not show improvement in physiological or clinical measures of ARDs in this study (57).
T137 21764-21935 Sentence denotes An additional pilot study (NCT101884051) investigated the effects of rhACE2 in human pulmonary arterial hypertension, which is characterized by reduced ACE2 activity (58).
T138 21936-22163 Sentence denotes Treatment with rhACE2 showed improved cardiac output that coincided with maximum suppression of plasma cytokines and reduction in nitrotyrosine levels, improved peripheral vascular resistance, and improved renal perfusion (58).
T139 22164-22234 Sentence denotes Ongoing clinical studies assessing the modulation of RAS axis include:
T140 22235-22449 Sentence denotes 1) the assessment of the relative activity of ACE and ACE2 in patients with diabetes following treatment with candesartan (Non-Insulin Dependent Diabetes Mellitus [NIDDM] and Angiotensin Converting Enzyme 2 [ACE2]:
T141 22450-22768 Sentence denotes Diabetic Patients Treated With Antihypertensive Drugs; NCT00192803); and 2) the overexpression of ACE2/Ang 1-7 in cardiac progenitor cells to assess for enhancement in reparative function and the potential to attenuate myocardial ischemia−induced cardiac damage (Cardiovascular Disease Protection Tissue; NCT02348515).
T142 22769-22975 Sentence denotes It is evident that targeting the ACE2/Ang1-7/Mas axis is going to be interesting in clinical settings because of the observed cardioprotective effects in the in vivo murine and in vitro cell culture models.
T143 22976-23121 Sentence denotes However, further investigation is required to demonstrate whether these favorable experimental effects could be translated into clinical benefit.
T144 23123-23164 Sentence denotes ACE2, COVID-19, and Cardiovascular Damage
T145 23165-23240 Sentence denotes Several reports have noted COVID-19 is associated with cardiac involvement.
T146 23241-23470 Sentence denotes In cohort studies of hospitalized patients with confirmed COVID-19, several patients presented with elevated troponin I, C-reactive protein, and N-terminal pro–B-type natriuretic peptide suggestive of myocardial injury (2,59,60).
T147 23471-23771 Sentence denotes Anecdotal studies have reported patients presenting with cardiac magnetic resonance imagining−verified acute myopericarditis with systolic dysfunction masquerading as diffuse ST-segment elevation myocardial infarction with elevated cardiac markers in the absence of obstructive coronary disease (59).
T148 23772-23933 Sentence denotes In a cohort study of 139 patients with COVID-19 hospitalized in Wuhan, China, 7.2% had acute myocardial injury, 8.7% had shock, and 16.7% had an arrhythmia (61).
T149 23934-24085 Sentence denotes Of the observed patients, those with cardiac injury were found to have a high risk of death both from time of symptom onset and time of admission (60).
T150 24086-24318 Sentence denotes As more epidemiological studies emerge from China, Italy, and other affected areas, more data will be available to elucidate the clinical presentation of patients and the cardiovascular damage associated with this novel coronavirus.
T151 24319-24453 Sentence denotes With regard to COVID-19, there are currently several clinical studies investigating the effects of RAS inhibition and ACE2 regulation.
T152 24454-24772 Sentence denotes An ongoing study will assess the impact of ACE inhibitor and ARB treatment on the severity and prognosis of patients with COVID-19 (Hypertension in Patients Hospitalized With COVID-19 [HT-COVID19], NCT04318301; ACE Inhibitors, Angiotensin II Type-I Receptor Blockers and Severity of COVID-19 [CODIV-ACE], NCT04318418).
T153 24773-25090 Sentence denotes Along these lines, there are 2 recently launched trials testing the effects of losartan among patients hospitalized with COVID-19 (Losartan for Patients With COVID-19 Requiring Hospitalization; NCT04312009) and those who are ambulatory (Losartan for Patients With COVID-19 Not Requiring Hospitalization; NCT04311177).
T154 25091-25467 Sentence denotes Further studies have been launched to evaluate the effect of continuation versus replacement (Coronavirus [COVID-19] ACEi/ARB Investigation [CORONACION]; NCT04330300) or withdrawal (ACE Inhibitors or ARBs Discontinuation in Context of SARS-CoV-2 Pandemic [ACORES-2]; NCT04329195) of RAS inhibitors on the clinical outcomes in patients with cardiovascular disease and COVID-19.
T155 25468-25689 Sentence denotes There is also an ongoing pilot study assessing the effects of rhACE2 treatment in patients with COVID-19 (Recombinant Human Angiotensin-converting Enzyme 2 [rhACE2] as a Treatment for Patients With COVID-19; NCT04287686).
T156 25690-25807 Sentence denotes Currently, there is no data to support any conclusive effects of the use of RAS inhibitors in patients with COVID-19.
T157 25809-25828 Sentence denotes ACE2 and SARS-CoV-2
T158 25829-26012 Sentence denotes SARS-CoV, which emerged in the Guangdong province, China, and SARS-CoV-2, which emerged in Wuhan, China are closely related beta-coronaviruses whose affected receptor is ACE2 (1,3,4).
T159 26013-26168 Sentence denotes At this time, it is unknown if the approximate 76% sequence similarity between these strains of viruses translates into similar biological properties (14).
T160 26169-26297 Sentence denotes Recent studies have confirmed COVID-19 exploits ACE2 for entry and thus may target a similar spectrum of cells as SARS-CoV (14).
T161 26298-26357 Sentence denotes SARS-CoV-2 binds to ACE2 via its spike (S) protein (13,14).
T162 26358-26462 Sentence denotes The surface unit S1, of the S protein binds to ACE2, which facilitates viral attachment to target cells.
T163 26463-26717 Sentence denotes Following receptor binding, the virus must gain access to host cytosol, which is accomplished by acid-dependent proteolytic cleavage of the S protein by cellular serine protease TMPRSS2, which is similar to S protein priming in SARS-CoV (14) (Figure 2 ).
T164 26718-26778 Sentence denotes Figure 2 Proposed Mechanism of Entry for SARS-CoV-2 Via ACE2
T165 26779-26894 Sentence denotes Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the catalytic site of ACE2 via its S protein.
T166 26895-27129 Sentence denotes To gain access to the host cytosol, the S protein undergoes acid dependent proteolytic cleavage by ACE2, tumor necrosis factor (TNF)-α, transmembrane protease serine 2 (TMPRRS2), which results in the formation of an S1 and S2 subunit.
T167 27130-27243 Sentence denotes S2 fusion peptide inserts into the membrane, which allows for clatherin-dependent endocytosis of ACE2-SARS-CoV-2.
T168 27244-27340 Sentence denotes Viral binding stimulates TNF-α and calmodulin inhibitors to promote ectodomain cleavage of ACE2.
T169 27341-27422 Sentence denotes ADAM 17 = disintegrin and metalloprotease 17; other abbreviations as in Figure 1.
T170 27423-27737 Sentence denotes Because of the sequence similarity between SARS-CoV and SARS-CoV-2, their affected receptor, and recently confirmed TMPRSS2-mediated viral entry, it is reasonable to hypothesize that SARS-CoV-2 may act similarly with respect to using host endocytosis machinery, subsequent virus propagation, and further infection.
T171 27738-27862 Sentence denotes Upon binding to ACE2, cleavage of the S protein at the S1/S2 sites and S2 allows for fusion of viral and cellular membranes.
T172 27863-27960 Sentence denotes SARS-CoV is then internalized and penetrates early endosomes in a clathrin-dependent manner (62).
T173 27961-28098 Sentence denotes Viral binding to ACE2 appears to affect TNF-α activity, which in the presence of calmodulin inhibitors promotes ectodomain cleavage (63).
T174 28099-28538 Sentence denotes In the case of SARS-CoV-2, it is possible this shedding is also mediated by TNF-α because 1 of the clinical features noted in patients with COVID-19 has been the presence of a cytokine storm with increased plasma concentrations of IL-2, IL-7, IL-10, granulocyte-colony stimulating factor (GCSF), interferon gamma-induced protein 10 (IP10), monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha (MIP1A), and TNF-α (2).
T175 28539-28638 Sentence denotes It is also possible that ACE2 shedding may be mediated by other cytokines dysregulated in COVID-19.
T176 28639-28753 Sentence denotes This shedding contributes to the down-regulation of membrane-bound ACE2 observed in severe acute lung injury (64).
T177 28754-28908 Sentence denotes Ectodomain shedding increases the concentration of plasma ACE2, which remains catalytically active, although the function of soluble ACE2 remains unclear.
T178 28909-29122 Sentence denotes In patients with advanced heart failure, plasma ACE2 activity is increased in direct proportion with worsening clinical status and reduction in ejection fraction and correlates with adverse clinical outcomes (65).
T179 29123-29564 Sentence denotes Because down-regulation of bound ACE2 is observed in severe acute lung injury (65) and after myocardial infarction (46), and concentrations of soluble ACE2 appear to correlate with clinical outcomes of patients with heart failure (30), it is possible to suggest that concentrations of soluble ACE2 may correlate to the extent of tissue damage sustained and may correlate to the degree by which systemic inflammatory pathways are upregulated.
T180 29565-29648 Sentence denotes There is some evidence to suggest soluble ACE2 is able to regulate systemic Ang II.
T181 29649-29802 Sentence denotes Clinical trials have shown rhACE2 could convert systemic Ang II to Ang 1-7 (57,58) and play some pathological, compensatory, or counter regulatory roles.
T182 29803-30139 Sentence denotes If SARS-CoV-2 does induce ACE2 ectodomain shedding, which results in the reduction of ACE2 entry sites on the infected cell, it is possible that following transcription S proteins fuse directly at the host cell membrane and directly promote infection of neighboring cells, which results in the formation of multinucleated syncytia (66).
T183 30140-30278 Sentence denotes Formation of multinucleated cells would allow the virus to spread without being detected or neutralized by virus-specific antibodies (66).
T184 30279-30456 Sentence denotes Otherwise, following replication and transcription, complete virion assembly in the Golgi would result in transportation of the virus in vesicles and release by exocytosis (66).
T185 30457-30611 Sentence denotes In the setting of full virion assembly and exocytosis, it is unclear if ACE2 ectodomain shedding would be favorable for further propagation and infection.
T186 30613-30674 Sentence denotes Medical Management in Cardiovascular Patients With SARS-CoV-2
T187 30675-30838 Sentence denotes Regardless of how SARS-CoV-2 completes virion assembly, it is clear that membrane-bound ACE2 would play a physiological role in the replication of the novel virus.
T188 30839-31049 Sentence denotes The question remains whether the use of ACE inhibitors, ARBs, and MRAs should be avoided in the setting of SARS-CoV infection because each agent (42, 43, 44, 45, 46,53) upregulates ACE2 expression and activity.
T189 31050-31321 Sentence denotes Lipopolysaccharide-induced acute lung injury mouse models exhibited decreased expression of ACE2, lung and inflammatory injury; however, this was ameliorated by the injection of cells transfected with ACE2 and resulted in the improvement of lung function and lung injury.
T190 31322-31440 Sentence denotes Treatment of these mice with ACE inhibitors and ARBs also alleviated lipopolysaccharide-induced pneumonic injury (67).
T191 31441-31555 Sentence denotes Previous studies showed the SARS-CoV S protein can exaggerate acute lung failure through dysregulation of the RAS.
T192 31556-31658 Sentence denotes However, SARS-CoV Spike–mediated lung failure could be rescued by inhibition of the AT1 receptor (67).
T193 31659-31943 Sentence denotes Again, adequate data on the effects of RAS inhibition in patients with COVID-19 is not available, and ongoing clinical and/or observations studies are being conducted (see previous mentions of NCT04318301, NCT04318418, NCT04312009, NCT04311177, NCT04287686, NCT04330300, NCT04329195).
T194 31944-32342 Sentence denotes If SARS-CoV-2 down-regulates membrane-bound ACE2 by promoting the ADAM17−mediated ectodomain shedding, resulting in increased concentrations of soluble ACE2 without compromising viral propagation, we hypothesize this would result in the overall down regulation of the ACE2/Ang1-7/Mas pathway, which would contribute to the severity of inflammation and systemic dysregulation observed in SARS-CoV-2.
T195 32343-32701 Sentence denotes Thus, in patients with cardiovascular disease and SARS-CoV-2, the use of ACE inhibitors, ARBs, or MRAs may be favorable as a method to endogenously upregulate ACE2 as a compensatory mechanism that provides anti-inflammatory, antifibrotic, and antithrombotic support as well as reduction in progression of vascular and/or cardiac remodeling and heart failure.
T196 32702-33100 Sentence denotes Several societies, including the American College of Cardiology, American Heart Association, Heart Failure Society of America (68), and European Society of Cardiology (69) have recommended continuing RAS antagonists because of the lack of conclusive data on a link between upregulation of systemic or tissue ACE2 and the increased susceptibility to COVID-19 in patients with cardiovascular disease.
T197 33101-33323 Sentence denotes Based on our review, we hypothesize cardiovascular patients with COVID-19 should remain on RAS inhibitors because of the protective effects of the ACE2 pathway until RAS blockade is proven to increase the risk of COVID-19.
T198 33325-33339 Sentence denotes Acknowledgment
T199 33340-33413 Sentence denotes The authors thank Kristen Amodio for her contribution during discussions.
T200 33414-33523 Sentence denotes The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
T201 33524-33745 Sentence denotes The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate.
T202 33746-33807 Sentence denotes For more information, visit the JACCauthor instructions page.
T203 33808-33900 Sentence denotes Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster onJACC.org.