Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Molecular Pathways Disturbances during COVID-19 Lead to Cardiomyocyte Necroptosis

These authors contributed equally to the work.
Version 1 : Received: 24 April 2023 / Approved: 25 April 2023 / Online: 25 April 2023 (04:06:34 CEST)

How to cite: Sotoudeheian, M.; Soleimani, M.; Farahmandian, N.; Mirahmadi, S. Molecular Pathways Disturbances during COVID-19 Lead to Cardiomyocyte Necroptosis. Preprints 2023, 2023040882. https://doi.org/10.20944/preprints202304.0882.v1 Sotoudeheian, M.; Soleimani, M.; Farahmandian, N.; Mirahmadi, S. Molecular Pathways Disturbances during COVID-19 Lead to Cardiomyocyte Necroptosis. Preprints 2023, 2023040882. https://doi.org/10.20944/preprints202304.0882.v1

Abstract

SARS-CoV-2 was detected in China in December 2019. Myocardial injury is a crucial presentation of COVID-19, based on the association of ACE-2 and SARS-CoV-2. Down-regulating ACE-2 decreases the cardioprotective effects of angiotensin, leading to a higher TNF-α activation. TNF-α causes the inflammatory response in the myocardial damage as an apoptotic inducer. Moreover, as an inducer of necroptosis, TNF-α binds to a part of TNF receptor 1, which involves receptor-interacting protein 1 (RIP1) and causes cell death through RIP1 inhibition and NF-κB stimulation, which are also done through Tpl-2. Calcineurin controls the Tpl-2-driven NFAT stimulation. Bcl-2 or Bcl-XL entirely blocks these pathways. Bcl-2 overexpression reduces FasL expression with a mechanism based on Bcl-2 inhibiting the NFAT. Moreover, the Fas/FasL system activates apoptosis in various cells. Bcl-XL stimulates Fas-related cell death. Additionally, TNF-α, as a part of inflammatory cytokine storms, indirectly interacts with NFAT/Bcl-2 through Tpl-2/NF-κB. Diversely, TNF-α and IL-1ẞ, the basis of inflammatory cytokine storms in COVID-19, can stimulate generating NO. Also, IL-2 is highly up-regulated in COVID-19 patients and stimulates NO generation in patients. TNF-α can provoke the generation of superoxides in neutrophils. A well-determined mechanism is the intracellular production of NO via calcium-calmodulin-dependent NO synthase (NOS). NO enhances NFAT’s calcium-dependent activity. Also, Intra/extracellular calcium exchange activates calcineurin and its related molecule, NFAT. Nitration provokes RIP1 necroptosis cascade, with respiratory complex I. Nitrites converse protection against ischemia-reperfusion injuries in the myocardium. Regulating this intrinsic molecular pathway can prevent the necroptosis of cardiomyocytes.

Keywords

COVID-19; Necroptosis; NFAT; NO; TNF-α; NF-κB

Subject

Medicine and Pharmacology, Cardiac and Cardiovascular Systems

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