Induced dysregulation of ACE2 by SARS-CoV-2 plays a key role in COVID-19 severity

Mehrabadi, Maryam Eskandari; Hemmati, Roohullah; Tashakor, Amin; Homaei, Ahmad; Yousefzadeh, Masoumeh; Karim, Helmet T.; Hosseinkhani, Saman

doi:10.1016/j.biopha.2021.111363

Cited by 55 publications

(38 citation statements)

References 243 publications

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“…These degradation peptides have a number of counterregulatory effects on angiotensin II [70]. It has been postulated that many clinical manifestations of COVID-19 are related to ACE2 down-regulation and subsequent angiotensin II accumulation [68]. This is confirmed by the observation of a direct correlation between COVID-19 severity and angiotensin II levels [72,73].…”

Section: Physiopathology Of Endothelial Dysfunction and Gender Differences In Covid-19mentioning

confidence: 94%

“…Overall, both genetic and hormonal factors could lead to the ACE2 over-expression among females [66,67]. This potentially compensates for the virus-induced down-regulation of ACE2, due to the endocytosis of the enzyme along with the viral particles [68] and to the up-regulation of a disintegrin and metalloproteinase 17 (ADAM17) deputized to the proteolytic cleavage of ACE2 [69].…”

Section: Physiopathology Of Endothelial Dysfunction and Gender Differences In Covid-19mentioning

confidence: 99%

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Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study

et al. 2021

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Background: Endothelial dysfunction has a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its disabling complications. We designed a case-control study to assess the alterations of endothelium-dependent flow-mediated dilation (FMD) among convalescent COVID-19 patients. Methods: COVID-19 patients referred to a Pulmonary Rehabilitation Unit within 2 months from swab test negativization were consecutively evaluated for inclusion and compared to controls matched for age, gender, and cardiovascular risk factors. Results: A total of 133 convalescent COVID-19 patients (81.2% males, mean age 61.6 years) and 133 matched controls (80.5% males, mean age 60.4 years) were included. A significantly lower FMD was documented in convalescent COVID-19 patients as compared to controls (3.2% ± 2.6 vs. 6.4% ± 4.1 p < 0.001), confirmed when stratifying the study population according to age and major clinical variables. Among cases, females exhibited significantly higher FMD values as compared to males (6.1% ± 2.9 vs. 2.5% ± 1.9, p < 0.001). Thus, no significant difference was observed between cases and controls in the subgroup analysis on females (6.1% ± 2.9 vs. 5.3% ± 3.4, p = 0.362). Among convalescent COVID-19 patients, FMD showed a direct correlation with arterial oxygen tension (rho = 0.247, p = 0.004), forced expiratory volume in 1 s (rho = 0.436, p < 0.001), forced vital capacity (rho = 0.406, p < 0.001), and diffusing capacity for carbon monoxide (rho = 0.280, p = 0.008). Overall, after adjusting for major confounders, a recent COVID-19 was a major and independent predictor of FMD values (β = −0.427, p < 0.001). Conclusions: Post-acute COVID-19 syndrome is associated with a persistent and sex-biased endothelial dysfunction, directly correlated with the severity of pulmonary impairment.

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Section: Physiopathology Of Endothelial Dysfunction and Gender Differences In Covid-19mentioning

confidence: 94%

Section: Physiopathology Of Endothelial Dysfunction and Gender Differences In Covid-19mentioning

confidence: 99%

Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study

et al. 2021

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“…ACE2 acts on numerous other substrates in the brain, including the endogenous opioid neuropeptides known as dynorphins. ( 36 ) ACE2 loss leading to unopposed bradykinin, neurotensin, and dynorphin levels could help explain increased vascular permeability, delirium, and high sedative requirements in COVID-19 patients ( 37 ). Preclinical studies show that the ACE2/angiotensin 1–7/MasR-axis affects cognition, anxiety, depression, and other mood disorders.…”

Section: The Prothrombotic State and The Cns (Impaired Large Vessel Or Microvascular Blood Flow)mentioning

confidence: 99%

Neurologic Manifestations of COVID-19 in Children: Emerging Pathophysiologic Insights

Schober

Pavia

Bohnsack

2021

Pediatric Critical Care Medicine

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In adults with COVID-19 (the disease caused by infection with severe acute respiratory syndrome coronavirus, SARS-CoV-2), the prevalence of acute neurologic symptoms (e.g., headaches, anosmia, seizure) and conditions (e.g., encephalopathy, stroke, delirium, encephalitis) ranges widely, from 4.4% to 100% of cases (1, 2). Neurologic manifestations in children younger than 18 years with COVID-19 is also relatively common. For example, in the United States, of nearly 3,700 cases, 17% had nonspecific neurologic conditions such as headache, fatigue, and myalgia, and 1% presented with encephalopathy, seizures, and meningeal signs (3). Worldwide, a report of nearly 1,400 pediatric patients described similar prevalence of headache (4%), anosmia (2%), seizures (0.7%), and cerebrovascular stroke (0.7%) (4).The pathophysiology of acute and postacute neurologic manifestations of COVID-19 is likely multifactorial. Each of the following mechanistic pathways could interactively or independently cause disease: 1) direct viral invasion and replication in the CNS, 2) large vessel or microvascular insufficiency due to vasoconstriction and/or occlusion, 3) nonspecific effects of severe systemic COVID-19 illness or treatment, and 4) immune system dysregulation and autoimmunity. VIRAL INVASION OF THE NERVOUS SYSTEMCellular invasion by the SARS-CoV-2 begins with binding of the viral spike protein to a transmembrane receptor, followed by viral membrane fusion with the cellular membrane after activation of the spike protein by cellular proteases.SARS-CoV-2 binds to the angiotensin-converting enzyme (ACE) 2 receptor, a protein coexpressed with the protease transmembrane serine protease 2 (TMPRSS2) in endothelial cells throughout the body. ACE2 is particularly abundant in the small intestine, kidney, lungs, and heart (5). ACE2 is also present in human adult and fetal brain, with highest expression in the pons and medulla oblongata (6). In mice, brain ACE2 protein is higher in the early postnatal period than in the adult, whereas ACE2 activity is similar (7). ACE2 is also expressed in components of the cerebral vasculature and blood-brain barrier (BBB): that is, the endothelium, pericytes, and contractile cells (8-10). Purkinje cells, cortical layer V neurons, astrocytes, and micrglia also express ACE2 and TMPRSS2 (10). SARS-CoV-2 may bind

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“…Remarkably, apelin peptides specifically induce ACE2 expression through the action of APJR 25 . Given its actions, it has been hypothesized that apelin, and possibly its ACE2‐metabolized peptides, may be protective in COVID‐19 through their cardioprotective mechanisms 26,27 . ACE2 has been found associated with SLC6A19 in the brush border of epithelial intestinal cells and the proximal kidney tubules 28,29 .…”

Section: Biology Of Ace2mentioning

confidence: 99%

Genetic and epigenetic control of ACE2 expression and its possible role in COVID‐19

Lima

Rocha

Moreira

2021

Cell Biochemistry & Function

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Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), is a pandemic that is claiming hundreds of thousands of lives around the world. Angiotensin‐converting enzyme‐2 (ACE2) is a key player in COVID‐19 due to its pivotal role in the SARS‐CoV‐2 infection. This enzyme is expressed throughout the body and the studies conducted so far have shown that its expression varies according to several factors, including cell type, sex, age, disease states and probably SARS‐CoV‐2 infection. Single‐nucleotide polymorphisms (SNPs) and epigenetic mechanisms, including DNA methylation, histone post‐translational modifications and microRNAs, impact ACE2 expression and may explain structural variation. The understanding of how genetic variants and epigenetic markers act to control ACE2 expression in health and disease states may contribute to comprehend several aspects of COVID‐19 that are puzzling researchers and clinicians. This review collects and appraises the literature regarding some aspects in the ACE2 biology, the expression patterns of this molecule, SNPs of the ACE2 gene and epigenetic mechanisms that may impact ACE2 expression in the context of COVID‐19.

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Induced dysregulation of ACE2 by SARS-CoV-2 plays a key role in COVID-19 severity

Cited by 55 publications

References 243 publications

Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study

Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study

Neurologic Manifestations of COVID-19 in Children: Emerging Pathophysiologic Insights

Genetic and epigenetic control of ACE2 expression and its possible role in COVID‐19

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