Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

Zamai, Loris

doi:10.3390/cells10030506

Cited by 23 publications

(48 citation statements)

References 92 publications

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“…Direct viral infection of perivenular hepatocytes and endothelial cells, the main ACE2-expressing cells in the liver, cannot be ruled out [ 87 ]. In this regard, hypoxic conditions upregulate ACE2 protein expression on human hepatocytes [ 88 ], thus increasing liver susceptibility to virus infection that could lead to a liver dysfunction and possibly to a liver-mediated hypercoagulatory state [ 27 , 89 ].…”

Section: Ace2 and Organ Tropism Of Sars-cov2mentioning

confidence: 99%

Lock, Stock and Barrel: Role of Renin-Angiotensin-Aldosterone System in Coronavirus Disease 2019

Zanza

Tassi

Romenskaya

et al. 2021

Cells

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Since the end of 2019, the medical-scientific community has been facing a terrible pandemic caused by a new airborne viral agent known as SARS-CoV2. Already in the early stages of the pandemic, following the discovery that the virus uses the ACE2 cell receptor as a molecular target to infect the cells of our body, it was hypothesized that the renin-angiotensin-aldosterone system was involved in the pathogenesis of the disease. Since then, numerous studies have been published on the subject, but the exact role of the renin-angiotensin-aldosterone system in the pathogenesis of COVID-19 is still a matter of debate. RAAS represents an important protagonist in the pathogenesis of COVID-19, providing the virus with the receptor of entry into host cells and determining its organotropism. Furthermore, following infection, the virus is able to cause an increase in plasma ACE2 activity, compromising the normal function of the RAAS. This dysfunction could contribute to the establishment of the thrombo-inflammatory state characteristic of severe forms of COVID-19. Drugs targeting RAAS represent promising therapeutic options for COVID-19 sufferers.

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Section: Ace2 and Organ Tropism Of Sars-cov2mentioning

confidence: 99%

Lock, Stock and Barrel: Role of Renin-Angiotensin-Aldosterone System in Coronavirus Disease 2019

Zanza

Tassi

Romenskaya

et al. 2021

Cells

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“…Therefore, there is the need to keep searching for new pharmacological therapies and more scientific efforts should be directed towards pharmacological approaches that, working downstream the infection pathways, are independent on virus variant. In this regard, clinical trials employing new safe pharmacological treatments for COVID-19 with a potentially effective mechanism of action that are not tested in clinical trials yet, such as chelating agents, bismuth based or other antiviral drugs, are urgently needed (see [27][28][29][30].…”

Section: The Possible Impact Of Emerging Sars-cov-2 Variants On Vaccine Efficacy Sars-cov-2 Infection Age-distribution and Severity And Tmentioning

confidence: 99%

“…The proposal of a new pharmacotherapy: the targeting of ACE2 and ADAM17 zinc-metalloproteases In previous works, we have highlighted that the binding of the SARS-CoV spike proteins to the zincmetalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity (27,28,31 ). Indeed, the interaction of ACE2 with spike protein of SARS-CoV is able to induce a cellular "protective" ACE2 shedding feedback response that initially limits viral entry (31 ).…”

Section: The Possible Impact Of Emerging Sars-cov-2 Variants On Vaccine Efficacy Sars-cov-2 Infection Age-distribution and Severity And Tmentioning

confidence: 99%

“…Indeed, the interaction of ACE2 with spike protein of SARS-CoV is able to induce a cellular "protective" ACE2 shedding feedback response that initially limits viral entry (31 ). However, an excessive systemic ACE2 activity produced by ACE2 shedding would be at the origin of COVID-19, which would be induced by positive feedback-loops initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger (see 27,28 ). Indeed, a few experimental models have shown that an upregulation of pathways downstream ACE2 activity (i.e.…”

Section: The Possible Impact Of Emerging Sars-cov-2 Variants On Vaccine Efficacy Sars-cov-2 Infection Age-distribution and Severity And Tmentioning

confidence: 99%

“…Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities can be proposed as therapy for COVID-19. In particular, zincchelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases (see 27,28 ). Several zinc-chelating agents as well as specific RAS pathway inhibitors (e.g., phytates, nicotianamine, zeolites, MLN-4760, Dx600, A779, aliskiren) and specific ADAM17 inhibitors (34 ) have been already proposed as anti-SARS-CoV-2 agents whose administration routes and safety concerns have been widely discussed in previous works (see27,28 ).…”

Section: The Possible Impact Of Emerging Sars-cov-2 Variants On Vaccine Efficacy Sars-cov-2 Infection Age-distribution and Severity And Tmentioning

confidence: 99%

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Possible influence of anti-vector immunity and SARS-CoV-2 variants on efficacy of ChAdOx1 nCoV-19 vaccine and the proposal of a new pharmacotherapy

Zamal

Rocchi

2021

Preprint

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The present work analyses in detail the published data on ChAdOx1 nCoV-19 vaccine and provides arguments for the involvement of anti-vector immunity and of SARS-CoV-2 variants on the efficacy of ChAdOx1 nCoV-19 vaccine. First, it is suggested that anti-vector immunity takes place as the regimen of homologous vaccination with ChAdOx1 nCoV-19 vaccine is applied and interferes with efficacy of the vaccine when the interval between prime and boost doses is less than three months. Second, longitudinal studies suggest that ChAdOx1 nCoV-19 vaccine provides sub-optimal efficacy against UK variant of SARS-CoV-2, which appears to have an increased transmissibility over the ancestral SARS-CoV-2 among vaccinated people. At the moment, ChAdOx1 nCoV-19 vaccine is able to reduce the severity of symptoms and transmissibility; however, if the vaccinated individuals do not maintain everyday preventive actions, they could turn into potential spreaders, thus accelerating the process of generation of new viral variants due to the selective pressure of immune response. Prediction and possible consequences of the SARS-CoV-2 evolution and repeated anti-SARS-CoV-2 vaccinations are discussed. Since the impact of emerging SARS-CoV-2 variants suggests that vaccines are unlikely to be effective in quickly solving the pandemic crisis, it is highlighted the need to keep searching for new and more efficacious pharmacotherapy for COVID-19, such as those targeting ACE2 and ADAM17 zinc-metalloprotease activities.

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Role of the RAAS in mediating the pathophysiology of COVID-19

Jasiczek,

Doroszko,

Trocha

et al. 2024

Pharmacol. Rep

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The renin-angiotensin-aldosterone system (RAAS) holds a position of paramount importance as enzymatic and endocrine homeostatic regulator concerning the water-electrolyte and acid-base balance. Nevertheless, its intricacy is influenced by the presence of various complementary angiotensins and their specific receptors, thereby modifying the primary RAAS actions. Angiotensin-converting enzyme 2 (ACE2) acts as a surface receptor for SARS-CoV-2, establishing an essential connection between RAAS and COVID-19 infection. Despite the recurring exploration of the RAAS impact on the trajectory of COVID-19 along with the successful resolution of many inquiries, its complete role in the genesis of delayed consequences encompassing long COVID and cardiovascular thrombotic outcomes during the post-COVID phase as well as post-vaccination, remains not fully comprehended. Particularly noteworthy is the involvement of the RAAS in the molecular mechanisms underpinning procoagulant processes throughout COVID-19. These processes significantly contribute to the pathogenesis of organ complications as well as determine clinical outcomes and are discussed in this manuscript.

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Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

Cited by 23 publications

References 92 publications

Lock, Stock and Barrel: Role of Renin-Angiotensin-Aldosterone System in Coronavirus Disease 2019

Lock, Stock and Barrel: Role of Renin-Angiotensin-Aldosterone System in Coronavirus Disease 2019

Possible influence of anti-vector immunity and SARS-CoV-2 variants on efficacy of ChAdOx1 nCoV-19 vaccine and the proposal of a new pharmacotherapy

Role of the RAAS in mediating the pathophysiology of COVID-19

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