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Review
. 2022 Nov 11;23(22):13895.
doi: 10.3390/ijms232213895.

The Renin-Angiotensin-Aldosterone System, Nitric Oxide, and Hydrogen Sulfide at the Crossroads of Hypertension and COVID-19: Racial Disparities and Outcomes

Tara Ranjbar  1 , Palak P Oza  1 , Khosrow Kashfi  1   2
Affiliations
Review

The Renin-Angiotensin-Aldosterone System, Nitric Oxide, and Hydrogen Sulfide at the Crossroads of Hypertension and COVID-19: Racial Disparities and Outcomes

Tara Ranjbar et al. Int J Mol Sci. .

Abstract

Coronavirus disease 2019 is caused by SARS-CoV-2 and is more severe in the elderly, racial minorities, and those with comorbidities such as hypertension and diabetes. These pathologies are often controlled with medications involving the renin-angiotensin-aldosterone system (RAAS). RAAS is an endocrine system involved in maintaining blood pressure and blood volume through components of the system. SARS-CoV-2 enters the cells through ACE2, a membrane-bound protein related to RAAS. Therefore, the use of RAAS inhibitors could worsen the severity of COVID-19's symptoms, especially amongst those with pre-existing comorbidities. Although a vaccine is currently available to prevent and reduce the symptom severity of COVID-19, other options, such as nitric oxide and hydrogen sulfide, may also have utility to prevent and treat this virus.

Keywords: ACE2; COVID-19; RAAS inhibitors; SARS-CoV-2; health disparities; hydrogen sulfide; hypertension; nitric oxide; renin–angiotensin system.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
SARS-CoV-2 entry into the host cell. As an enveloped virus, SARS-CoV-2 can enter the host cell through one of two pathways—pathway #1, endosomal entry and pathway #2, direct cell surface entry. In both entry forms, the S protein binds to the ACE2 receptor and must be primed and activated by proteases at the S1/S2 and S2’ site. SARS-CoV-2 infection results in the downregulation of the ACE2 receptor, leading to an increase in Ang II and decrease in its conversion to Ang-(1-7). In pathway #1, SARS-CoV-2 undergoes clathrin-mediated endocytosis, and is primed by host protease Cathepsin L present in the endolysosome, followed by membrane fusion and release of viral genomic material. In pathway #2, the S protein is cleaved by TMPRSS2 at the cell membrane, where it directly fuses and releases viral RNA without entering an endolysosome. Both pathways join in the host cytoplasm, where a viral polymerase is translated, followed by RNA replication, structural protein translation, viral assembly, and release of progeny virus that continue to spread the infection to other cells. SARS-CoV-2 infection leads to respiratory compromise by causing lung injury, results in excessive inflammation with overactivation of leukocytes and production of inflammatory mediators, results in direct and inflammation-mediated damage to the endothelium, and induces a pro-thrombotic state. Reproduced with permission from Elsevier: Nitric Oxide, 128 (2022), 72–102 [71]. Abbreviations: ACE2, angiotensin-converting enzyme 2; Ang, angiotensin; S protein, spike protein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane serine protease 2.
Figure 2
Figure 2
Interactions between RAAS, NO, and H2S. The RAAS consists of two main axes, the pro-inflammatory and vasoconstrictive ACE-Ang II pathway, and the anti-inflammatory, vasorelaxant ACE2-Ang-(1-7) pathway, both of which differently affect NO and H2S bioavailability. Ang II uses AT1R and AT2R to exert a variety of effects upon NO bioavailability; there are reports of Ang II increasing NOS activity while simultaneously increasing the production of ROS through NADPH oxidase, resulting in NOS uncoupling and a net decrease in NO bioavailability over time despite increased production and release. Ang II also inhibits sGC and increases the activity of some PDEs, diminishing the function of the NO signaling pathway. On the other hand, Ang-(1-7) augments NO bioavailability both by reducing ROS and by stimulating NOS activity. In return, NO downregulates ACE and AT1R, reducing RAAS activation. There are also reports of the RAAS affecting H2S bioavailability, where increasing Ang II decreased H2S bioavailability by downregulating CSE and CBS. Measures to increase H2S bioavailability reduce traditional RAAS activation, inhibiting or downregulating renin release, ACE, AT1R, and ROS levels while increasing ACE2 activity to increase the function of the anti-inflammatory axis of the RAAS. Both gasotransmitters also interact to reinforce the other’s increase in bioavailability. Thus, NO and H2S both act to reduce RAAS overactivation, serving as anti-inflammatory, antioxidant, and vasorelaxant mediators. Note: black arrows show effects of RAAS on NO and H2S, green arrows show effects of the gasotransmitters on components of RAAS. Abbreviations: ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; Ang, angiotensin; AT1R, angiotensin II type 1 receptor; AT2R, angiotensin II type 2 receptor; CBS, cystathionine β-synthase; CSE, Cystathionine γ-Lyase; H2S, hydrogen sulfide; NADPH oxidase, nicotinamide adenine dinucleotide phosphate oxidase; NEP, neutral endopeptidase; NO, nitric oxide; NOS, nitric oxide synthase; PDEs, phosphodiesterases; RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; sGC, soluble guanylyl cyclase.
Figure 3
Figure 3
NO and H2S applications in COVID-19. NO and H2S are antiviral agents with promise for inhibiting SARS-CoV-2 infection through interference with entry, replication, and release. Both gasotransmitters also have potential applications in later-stage management of COVID-19. NO and H2S demonstrate the ability to inhibit leukocyte adhesion to the endothelium, reduce levels of pro-inflammatory cytokines, curtail excessive iNOS activity, and overall reduce inflammatory damage. These properties, combined with their vaso- and bronchodilator actions in the pulmonary system, serve to reduce the need for mechanical ventilation and alleviate respiratory compromise. Additionally, NO and H2S downregulate the classical RAAS signaling pathway and its related pro-inflammatory shift by inhibiting Ang II and AT1R. As a result, NO and H2S may have significant potential in the management of COVID-19, a disease recognized for causing hyperinflammatory conditions and respiratory compromise and for having greater severity where the RAAS is imbalanced. Abbreviations: Ang II, angiotensin II; AT1R, angiotensin II type 1 receptor; COVID-19; coronavirus disease 2019; H2S, hydrogen sulfide; NO, nitric oxide; RAAS, renin–angiotensin–aldosterone system; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
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References

    1. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5. - DOI - PMC - PubMed
    1. Godeau D., Petit A., Richard I., Roquelaure Y., Descatha A. Return-to-work, disabilities and occupational health in the age of COVID-19. Scand. J. Work Environ. Health. 2021;47:408–409. doi: 10.5271/sjweh.3960. - DOI - PMC - PubMed
    1. CDC About COVID-19: People with Certain Medical Conditions. [(accessed on 17 August 2022)]; Available online: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-....
    1. Walubita T., Beccia A., Boama-Nyarko E., Goulding M., Herbert C., Kloppenburg J., Mabry G., Masters G., McCullers A., Forrester S. Aging and COVID-19 in Minority Populations: A Perfect Storm. Curr. Epidemiol. Rep. 2021;8:63–71. doi: 10.1007/s40471-021-00267-4. - DOI - PMC - PubMed
    1. Wilder J.M. The Disproportionate Impact of COVID-19 on Racial and Ethnic Minorities in the United States. Clin. Infect. Dis. 2021;72:707–709. doi: 10.1093/cid/ciaa959. - DOI - PMC - PubMed