The Two Faces of ACE2: The Role of ACE2 Receptor and Its Polymorphisms in Hypertension and COVID-19

Bosso, Mira; Thanaraj, Thangavel Alphonse; Abu‐Farha, Mohamed; Alanbaei, Muath; Abubaker, Jehad; Al-Mulla, Fahd

doi:10.1016/j.omtm.2020.06.017

Cited by 138 publications

(133 citation statements)

References 41 publications

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“…For example, ACE2 gene variants have been associated with risk for hypertension, dyslipidemia, type 2 diabetes and cardiovascular dysfunction [138,[155][156][157][158][159][160][161]. Most of these variants are intronic and located in splice-site junctions or in enhancer regions while the others are placed in the 3' UTR promoter region, suggesting their involvement in the structure/function and expression of ACE2 gene [138]. On the other hand, COVID-19 has similar risk factors of obstructive sleep apnea (OSA), suggesting a possible association between OSA and COVID-19 [164].…”

Section: Correlation Of Pre-existing Circulating Ace2 Activity and Inmentioning

confidence: 99%

“…Furthermore, subjects with hypertension, diabetes, dyslipidemia, or plaques also had significantly increased circulating ACE2 activity when compared with those without these pathologies [ 96 ]. Notably, hypertensive (the most frequent comorbidity with COVID-19) and diabetic patients are often treated with ACE inhibitors (ACEIs) and/or with ARBs, suggesting a possible positive correlation [ 135 , 136 , 137 , 138 ]. Interestingly, circulating ACE2 activity is significantly increased in subjects on therapy with ARBs or taking oral antidiabetic agents as compared with non-treated patients, while treatment with ACEIs and cholecalciferol had no significant influence on circulating ACE2 activity [ 96 ].…”

Section: Correlation Of Pre-existing Circulating Ace2 Activity Andmentioning

confidence: 99%

“…In this regard, different organism predisposition to infections including SARS-CoV-2 or to pathologies associated with an increased risk to develop severe forms of SARS-CoV-2 infection might depend not only on genetic ACE2 polymorphisms and organ-specific ACE2 gene/protein expression [ 138 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 ] but also on anatomical and environmental factors. For example, ACE2 gene variants have been associated with risk for hypertension, dyslipidemia, type 2 diabetes and cardiovascular dysfunction [ 138 , 155 , 156 , 157 , 158 , 159 , 160 , 161 ]. Most of these variants are intronic and located in splice-site junctions or in enhancer regions while the others are placed in the 3’ UTR promoter region, suggesting their involvement in the structure/function and expression of ACE2 gene [ 138 ].…”

Section: Correlation Of Pre-existing Circulating Ace2 Activity Andmentioning

confidence: 99%

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The Yin and Yang of ACE/ACE2 Pathways: The Rationale for the Use of Renin-Angiotensin System Inhibitors in COVID-19 Patients

Zamai

2020

Cells

139

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The article describes the rationale for inhibition of the renin-angiotensin system (RAS) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent positive feedback-loop mechanisms. Based purely on experimental studies in which RAS pathway inhibitors were administered in vivo to humans/rodents, a reasonable hypothesis of using inhibitors that block both ACE and ACE2 zinc metalloproteases and their downstream pathways in COVID-19 patients will be proposed. In particular, metal (zinc) chelators and renin inhibitors may work alone or in combination to inhibit the positive feedback loops (initially triggered by SARS-CoV-2 and subsequently sustained by hypoxia independently on viral trigger) as both arms of renin-angiotensin system are upregulated, leading to critical, advanced and untreatable stages of the disease.

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Section: Correlation Of Pre-existing Circulating Ace2 Activity and Inmentioning

confidence: 99%

Section: Correlation Of Pre-existing Circulating Ace2 Activity Andmentioning

confidence: 99%

Section: Correlation Of Pre-existing Circulating Ace2 Activity Andmentioning

confidence: 99%

See 1 more Smart Citation

The Yin and Yang of ACE/ACE2 Pathways: The Rationale for the Use of Renin-Angiotensin System Inhibitors in COVID-19 Patients

Zamai

2020

Cells

139

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“…It should be pointed out that the great clinical impact of this issue has encouraged discussions that are largely based on indirect speculations rather than objective data. Data from appropriate clinical trials are still lacking, although a retrospective multicenter study on more than 1,000 patients with COVID-19 and hypertension treated with ACEI or ARB revealed that the use of these drugs was associated with lower mortality from all cause (Bosso et al, 2020).…”

Section: The Controversial Role Of Ace2 Expressionmentioning

confidence: 99%

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives

Saponaro

Rutigliano

Sestito

et al. 2020

Front. Mol. Biosci.

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Angiotensin-converting enzyme 2 (ACE2) is related to ACE but turned out to counteract several pathophysiological actions of ACE. ACE2 exerts antihypertensive and cardioprotective effects and reduces lung inflammation. ACE2 is subjected to extensive transcriptional and post-transcriptional modulation by epigenetic mechanisms and microRNAs. Also, ACE2 expression is regulated post-translationally by glycosylation, phosphorylation, and shedding from the plasma membrane. ACE2 protein is ubiquitous across mammalian tissues, prominently in the cardiovascular system, kidney, and intestine. ACE2 expression in the respiratory tract is of particular interest, in light of the discovery that ACE2 serves as the initial cellular target of severe acute respiratory syndrome (SARS)-coronaviruses, including the recent SARS-CoV2, responsible of the COronaVIrus Disease 2019 (COVID-19). Since the onset of the COVID-19 pandemic, an intense effort has been made to elucidate the biochemical determinants of SARS-CoV2-ACE2 interaction. It has been determined that SARS-CoV2 engages with ACE2 through its spike (S) protein, which consists of two subunits: S1, that mediates binding to the host receptor; S2, that induces fusion of the viral envelope with the host cell membrane and delivery of the viral genome. Owing to the role of ACE2 in SARS-CoV2 pathogenicity, it has been speculated that medical conditions, i.e., hypertension, and/or drugs, i.e., ACE inhibitors and angiotensin receptor blockers, known to influence ACE2 density could alter the fate of SARS-CoV-2 infection. The debate is still open and will only be solved when results of properly designed experimental and clinical investigations will be made public. An interesting observation is, however that, upon infection, ACE2 activity is reduced either by downregulation or by shedding. These events might precipitate the so-called "cytokine storm" that characterizes the most severe COVID-19 forms. As evidence accumulates, ACE2 appears a druggable target in the attempt to limit virus entry and replication. Strategies aimed at blocking ACE2 with antibodies, small molecules or peptides, or at neutralizing the virus by competitive binding with exogenously administered ACE2, are currently under investigations. In this review, we will present an overview of the state-of-the-art knowledge on ACE2 biochemistry and pathophysiology, outlining open issues in the context of COVID-19 disease and potential experimental and clinical developments.

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“…Thereafter the virus disassembles and viral genome is released into the cytoplasm of host cells. During SAR-CoV-2 infection, binding of spike protein to ACE2 has been proposed to resulting in ACE2 shedding from cell surface ( Bosso et al, 2020 ). ACE2 is a member of renin–angiotensin system (RAS), acting as a key negative regulator of ACE via degrading angiotensin (Ang) II into Ang-(1-7) ( Zhang and Baker, 2017 ).…”

Section: The Pathophysiology Of Covid-19mentioning

confidence: 99%

Transplantation of Mesenchymal Stem Cells: A Potential Adjuvant Therapy for COVID-19

Zhu

Geng

et al. 2020

Front. Bioeng. Biotechnol.

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen for coronavirus disease-2019 (COVID-19), which has posed an increasing serious public health threat. However, still there are no approved antiviral agents or vaccines available yet. Mesenchymal stem cells (MSCs) are emerging as a novel promising adjuvant therapy for the attenuation of COVID-19 based on its putative pathogenesis. MSCs may exert anti-inflammatory, immunomodulatory, anti-apoptotic, as well as regenerative effects through a series of mechanisms. Remarkably, MSCs may be resistant to virus infection, which is fundamental for the treatment of COVID-19. The beneficial therapeutic effects of MSCs have been preliminarily proved to be safe and efficacious for the treatment of COVID-19 in current clinical trials. This work aims to review the beneficial effects of MSCs in treating ALI/ARDS, which provides novel insight into the potential therapeutic strategies against COVID-19. However, further research is warranted regarding both safety and efficacy of MSCs.

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The Two Faces of ACE2: The Role of ACE2 Receptor and Its Polymorphisms in Hypertension and COVID-19

Cited by 138 publications

References 41 publications

The Yin and Yang of ACE/ACE2 Pathways: The Rationale for the Use of Renin-Angiotensin System Inhibitors in COVID-19 Patients

The Yin and Yang of ACE/ACE2 Pathways: The Rationale for the Use of Renin-Angiotensin System Inhibitors in COVID-19 Patients

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives

Transplantation of Mesenchymal Stem Cells: A Potential Adjuvant Therapy for COVID-19

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