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Vaccines R&D 08-11 final2.pdf
1. A Homeostatic Approach to COVID-19; preserving physiological boundaries of RAS
by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
2. Reza Nejat, M. D., FCCM,
Anesthesiology and Critical Care Dept., Laleh Hospital,
Anti-Doping, Nutrition and Metabolism Consultant, World Powerlifting Ltd., Eurasia Division (Asia, Iran),
Melbourne, Australia,
Former Assistant Professor, SBMU,
N1
4. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
HOMEOSTASIS
Coined by Walter B.
Cannon
Self regulating processes
maintaining the internal
stability and function of
organisms facing constant
changes of their external
environment
Endow the organism with
buffering protective
mechanisms:
Required for free independent life
Billman, G. E., Frontiers in Physiology, 2020: p.200
5. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
HOMEOSTASIS:
Intricate network of activators
and inhibitors
Modification of these network:
Activates latent metabolic
or signaling pathways
Induces unpredicted
interactions
Deviates the set points
6. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Oldstone, M.B., et al., Science, 1982. 218: p. 1125-1127
7. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Kotzamanis, K., et al., Medical Microbiol Immunol, 2015. 204: p.
395-407
8. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Immunopathologic dyshomeostatic
characteristics of severe COVID-19
Impaired production of IFN-I,
Overwhelming Inflammatory
reactions,
Lymphopenia ,
Lymphocytic exhaustion,
Delayed triggering of adaptive
immunity,
9. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Nejat, R., M.F. Torshizi, and D.J. Najafi, Vaccines, 2023. 11(2): p. 204
10. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Nejat, R., M.F. Torshizi, and D.J. Najafi, Vaccines, 2023. 11(2): p. 204
11. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
RAS components and inflammation
Ang II receptor was found on
human mononuclear cells (1978)
Mϕ in granuloma induced by
schistosoma egg (1984)
Ang I, Ang II, ACE were found in
Hepatic granuloma induced by
schistosoma egg (1981, 1983)
Pretreatment with captopril
Decreased Granuloma induced by
BCG (1982)
Chemoattractant effect of Ang II
Rat peritoneal Mϕ (1980, 1983)
12. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Systemic RAS
Endocrine system
BP regulation
Water and electrolyte balance
Local tissue RAS (1971)
Multiple paracrine/autocrine
effects:
Cell growth, proliferation,
differentiation, migration, apoptosis
Oxidative metabolism,
Adipogenesis
13. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Intra-cellular RAS
Found in some types of cells (?)
De novo synthesis (high glucose)
Cellular uptake
nucleus and cytoplasm
Intracrine effects
Mediated by AT1R and AT2R
Growth of VSMC
Cell proliferation (PI3K, ERK)
Increase [Ca2+]i
♣ Influx from EC
♣ From intracellular stores
14. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Ang II increases: (pro-inflammatory effects)
Adhesion molecules (ICAM, VCAM),
Cytokines (TNF-α, IL-6, CRP),
Chemokines (MCP-1, IL-8, MIF),
Ang II interrupts:
Insulin anti-inflammatory effects
Ang II promotes:
Prothrombotic state (PAI-1),
Oxidative stress (NADPH oxidase)
Dandona, P., et al., Journal of human hypertension, 2007. 21(1): p. 20-27
15. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Angiotensin receptor blockers
Suppress pro-inflammatory mediators,
(TNF-α, IL-6, MCP-1, PAI-1)
Increase I ĸB (inhibitor of NF-ĸB),
Decreases CRP,
Downregulates ROS,
Reduce insulin resistance
modest PPAR-γ activity
Increase adiponectin
Dandona, P., et al., Journal of human hypertension, 2007. 21(1): p. 20-27
16. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
RAS components in Human T
and NK cells, DC and
Monocytes:
Renin and Renin Receptor,
Angiotensinogen,
ACE
Angiotensin I (Ang I),
Angiotensin II (Ang II),
Jurewicz, M., et al. Journal of the American Society of
Nephrology, 2007. 18(4): p. 1093-1102.
17. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Jurewicz, M., et al. Journal of the American Society of
Nephrology, 2007. 18(4): p. 1093-1102.
Ang II and its precursors:
Shows mitogenic properties
CD8+ T and NK(presence)
Stimulate TCR-specific cells
proliferation
AT1R, AT2R are involved,
Another unidentified Ang II
receptor???
18. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Jurewicz, M., et al. Journal of the American Society of
Nephrology, 2007. 18(4): p. 1093-1102.
Ang II
ratio of IFN-γ/IL-4
Th1/Th2 cytokines,
Type I Mϕ
RANTES
♣ Shows chemotactic
properties
19. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
T cells and ACE2 expression
T cells express ACE2 molecules (almost
1000)
When activated, T cells express more ACE2
molecules
SARS-CoV-2 replication post-entry into T cells
is restricted and does not produce
infectious virus
Welch, J.L., et al., The Journal of Infectious Diseases,
2022. 225(5): p. 810-819
20. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Ang II stimulates (in DCs):
Maturation,
Migration,
Cytokine secretion
DC-mediated T cell proliferation
Through NF-kB/ERK1-2/STAT1
pathway
Meng, Y., et al., Cellular Physiology and Biochemistry,
2017. 42(4): p. 1550-1558
21. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Endogenous Ang II:
produced in T cells,
Activates T cells,
Induces TNF-α
through NOX- mediated
ROS production
Hoch, N.E., et al., Am. J. Physiology-Regulatory, Integrative
and Comparative Physiology, 2009. 296(2): p. R208-R216
22. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Hoch, N.E., et al., Am. J. Physiology-Regulatory, Integrative
and Comparative Physiology, 2009. 296(2): p. R208-R216
Endogenous Ang II:
Slightly more in CD4+ than
CD8+
AT1R and AT2R both contribute
to TNF-α production
Losartan (AT1R antagonist),
PD123319 (AT2R antagonist)*,
decrease TNF-α by 30%
23. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Endogenous Ang II:
Induces mitochondrial oxidative
damage
Nox/PKC pathway
Increase ROS
Activation of mitoKATP
channels
Diminished NO availability
Doughan, A.K., et al., Circulation research, 2008. 102(4): p. 488-496.
24. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Endogenous Ang II:
Inhibits alveolar fluid clearance
dysregulates ENaC expression
via AT1 receptors,
contribute to alveolar filling
and pulmonary edema in
LPS-induced ALI
Deng, J., et al., Canadian respiratory journal, 2012. 19: p. 311-318
25. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
March 2020
A video clip was uploaded in youtube:
https://youtu.be/kpyDrxw1kAI
“Losartan may subside ARDS in COVID-
19”
A case report of a patient with COVID-
19 in whom serial Lung CT scan
showed improvement of lung density
improved with losartan.
26. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
An in Silico study and a review
SARS-CoV-2 infection:
Downregulation of ACE2
Overzealous activation of local and
cellular Ang II/AT1R/Nox
Losartan (AT1R antagonist) and Imatinib:
“we have demonstrated that
losartan and imatinib could distort
the binding site of SARSCoV2 RBD
to ACE2.”
27. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
An in Silico study and a review
SARS-CoV-2 infection:
Downregulation of ACE2
Overzealous activation of local and
cellular Ang II/AT1R/Nox
Losartan (AT1R antagonist) and Imatinib:
“we have demonstrated that
losartan and imatinib could distort
the binding site of SARSCoV2 RBD
to ACE2.”
28. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
An in vitro cell culture study
Losartan (AT1R antagonist)
“Importantly, losartan treatment of
Vero E6 cells prior to and after
SARS-CoV-2 infection inhibited the
virus replication.”
29. by: Reza Nejat, M. D., FCCM; Anti‐Doping, Nutrition, Metabolism Consultant
A Homeostatic Approach to COVID-19;
preserving physiological boundaries of RAS
Conclusion
Considering the dyshomeostatic impact of
viral infections on host cells preserving
homeostatic balance of RAS in patients
with COVID-19 seems quite rational to be
considered as a promising therapeutic
strategy.
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