Circulating ACE2 activity predicts mortality and disease severity in hospitalized COVID-19 patients

Fagyas, Miklós; Fejes, Zsolt; Sütő, Renáta; Nagy, Zsuzsanna; Székely, Borbála; Pócsi, Marianna; Ivády, Gergely; Bíró, E; Bekő, Gabriella; Nagy, Attila; Kerekes, György; Szentkereszty, Zoltán; Papp, Zoltán; Tóth, Attila; Kappelmayer, János; Nagy, Béla

doi:10.1016/j.ijid.2021.11.028

Cited by 63 publications

(70 citation statements)

References 32 publications

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“…First, infection reduces ACE2 activity in the lungs due to cell death and shedding of cellular ACE2 through the action of proteases (Kuba et al , 2005; Haga et al , 2008; Heurich et al , 2014). This causes massive dysregulation of the RAAS, with large increases in serum Ang-II and serum sACE2 (Fagyas et al , 2022; Kragstrup et al , 2021; Filbin et al , 2021; Lundström et al , 2021; Reindl-Schwaighofer et al , 2021; Wu et al , 2020; Liu et al , 2020), although much of the serum sACE2 may have low catalytic activity as well as low S affinity and avidity due to proteolysis within the ACE2 collectrin-like dimerization domain. These serum markers are highly correlated with disease severity and elevated Ang-II may contribute to vasoconstriction, thrombophilia, microthrombosis, and respiratory failure.…”

Section: Introductionmentioning

confidence: 99%

An engineered ACE2 decoy receptor can be administered by inhalation and potently targets the BA.1 and BA.2 omicron variants of SARS-CoV-2

Zhang

Narayanan

Cooper

et al. 2022

Preprint

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Monoclonal antibodies targeting the SARS-CoV-2 spike (S) glycoprotein neutralize infection and are efficacious for the treatment of mild-to-moderate COVID-19. However, SARS-CoV-2 variants have emerged that partially or fully escape monoclonal antibodies in clinical use. Notably, the BA.2 sublineage of B.1.1.529/omicron escapes nearly all monoclonal antibodies currently authorized for therapeutic treatment of COVID-19. Decoy receptors, which are based on soluble forms of the host entry receptor ACE2, are an alternative strategy that broadly bind and block S from SARS-CoV-2 variants and related betacoronaviruses. The high-affinity and catalytically active decoy sACE22.v2.4-IgG1 was previously shown to be effective in vivo against SARS-CoV-2 variants when administered intravenously. Here, the inhalation of sACE22.v2.4-IgG1 is found to increase survival and ameliorate lung injury in K18-hACE2 transgenic mice inoculated with a lethal dose of the virulent P.1/gamma virus. Loss of catalytic activity reduced the decoy's therapeutic efficacy supporting dual mechanisms of action: direct blocking of viral S and turnover of ACE2 substrates associated with lung injury and inflammation. Binding of sACE22.v2.4-IgG1 remained tight to S of BA.1 omicron, despite BA.1 omicron having extensive mutations, and binding exceeded that of four monoclonal antibodies approved for clinical use. BA.1 pseudovirus and authentic virus were neutralized at picomolar concentrations. Finally, tight binding was maintained against S from the BA.2 omicron sublineage, which differs from S of BA.1 by 26 mutations. Overall, the therapeutic potential of sACE22.v2.4-IgG1 is further confirmed by inhalation route and broad neutralization potency persists against increasingly divergent SARS-CoV-2 variants.

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Section: Introductionmentioning

confidence: 99%

An engineered ACE2 decoy receptor can be administered by inhalation and potently targets the BA.1 and BA.2 omicron variants of SARS-CoV-2

Zhang

Narayanan

Cooper

et al. 2022

Preprint

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“…As discussed above for non-COVID ARDS, low Ang II plasma levels, especially if they are lower than the Ang I levels, may be caused by reduced ACE activity or by increased processing of Ang II into Ang 1–7 by ACE2 ( Krenn et al, 2020 ) or POP ( Triposkiadis et al, 2021 ). Increased ACE2 levels in the blood of patients with COVID-19 have already been described by several studies using ELISA as well as mass spectrometry-based assays ( Fagyas et al, 2021 ; Gerard et al, 2021 ; Lundstrom et al, 2021 ; Patel et al, 2021 ; Reindl-Schwaighofer et al, 2021 ; Wang et al, 2021 )., and were higher in more severely ill patients ( Fagyas et al, 2021 ; Patel et al, 2021 ; Reindl-Schwaighofer et al, 2021 ). An increasing trend in ACE2 plasma levels within 7 days from hospital admission indicated a higher 90-day mortality ( Wang et al, 2021 ).…”

Section: The Renin-angiotensin System In Covid-19mentioning

confidence: 79%

The Renin-Angiotensin System as a Component of Biotrauma in Acute Respiratory Distress Syndrome

et al. 2022

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Acute respiratory distress syndrome (ARDS) is a major concern in critical care medicine with a high mortality of over 30%. Injury to the lungs is caused not only by underlying pathological conditions such as pneumonia, sepsis, or trauma, but also by ventilator-induced lung injury (VILI) resulting from high positive pressure levels and a high inspiratory oxygen fraction. Apart from mechanical factors that stress the lungs with a specific physical power and cause volutrauma and barotrauma, it is increasingly recognized that lung injury is further aggravated by biological mediators. The COVID-19 pandemic has led to increased interest in the role of the renin-angiotensin system (RAS) in the context of ARDS, as the RAS enzyme angiotensin-converting enzyme 2 serves as the primary cell entry receptor for severe acute respiratory syndrome (SARS) coronavirus (CoV)-2. Even before this pandemic, studies have documented the involvement of the RAS in VILI and its dysregulation in clinical ARDS. In recent years, analytical tools for RAS investigation have made major advances based on the optimized precision and detail of mass spectrometry. Given that many clinical trials with pharmacological interventions in ARDS were negative, RAS-modifying drugs may represent an interesting starting point for novel therapeutic approaches. Results from animal models have highlighted the potential of RAS-modifying drugs to prevent VILI or treat ARDS. While these drugs have beneficial pulmonary effects, the best targets and application forms for intervention still have to be determined to avoid negative effects on the circulation in clinical settings.

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“…On the one hand, ACE2 is a SARS-CoV-2 entry receptor, and increased ACE2 expression may facilitate virus entry into cells [ 1 , 2 , 3 ]. On the other hand, viral binding reduces ACE2 levels at the cell surface, and the shift of the RAS balance towards the deleterious over the protective axis (increase in the ACE/ACE2 ratio) may lead to a progression of disease severity ( Figure 3 ) [ 95 , 96 ]. High ACE/ACE2 ratios occur in males, geriatric, and smoking patients, and many pathologies (especially cardiovascular, pulmonary, and renal diseases and obesity) are recognized as comorbidities that may aggravate the COVID-19 infection.…”

Section: Resultsmentioning

confidence: 99%

Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance

Mińczuk

Baranowska-Kuczko

Krzyżewska

et al. 2022

IJMS

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This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT1 receptors (AT1Rs) by angiotensin II (Ang II) can release endocannabinoids that, by acting at cannabinoid CB1 receptors (CB1Rs), modify the response to AT1R stimulation. CB1R blockade may enhance AT1R-mediated responses (mainly vasoconstrictor effects) or reduce them (mainly central nervous system-mediated effects). The final effects depend on whether stimulation of CB1Rs and AT1Rs induces opposite or the same effects. Second, CB1R blockade may diminish AT1R levels. Third, phytocannabinoids modulate angiotensin-converting enzyme-2. Additional studies are required to clarify (1) the existence of a cross-talk between the protective axis of the RAS (Ang II—AT2 receptor system or angiotensin 1-7—Mas receptor system) with components of the endocannabinoid system, (2) the influence of Ang II on constituents of the endocannabinoid system and (3) the (patho)physiological significance of AT1R-CB1R heteromerization. As a therapeutic consequence, CB1R antagonists may influence effects elicited by the activation or blockade of the RAS; phytocannabinoids may be useful as adjuvant therapy against COVID-19; single drugs acting on the (endo)cannabinoid system (cannabidiol) and the RAS (telmisartan) may show pharmacokinetic interactions since they are substrates of the same metabolizing enzyme of the transport mechanism.

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Circulating ACE2 activity predicts mortality and disease severity in hospitalized COVID-19 patients

Cited by 63 publications

References 32 publications

An engineered ACE2 decoy receptor can be administered by inhalation and potently targets the BA.1 and BA.2 omicron variants of SARS-CoV-2

An engineered ACE2 decoy receptor can be administered by inhalation and potently targets the BA.1 and BA.2 omicron variants of SARS-CoV-2

The Renin-Angiotensin System as a Component of Biotrauma in Acute Respiratory Distress Syndrome

Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance

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