The dual impact of ACE2 in COVID-19 and ironical actions in geriatrics and pediatrics with possible therapeutic solutions

Abstract

The novel corona virus disease has shaken the entire world with its deadly effects and rapid transmission rates, posing a significant challenge to the healthcare authorities to develop suitable therapeutic solution to save lives on earth. The review aims to grab the attention of the researchers all over the globe, towards the role of ACE2 in COVID-19 disease. ACE2 serves as a molecular target for the SARS-CoV-2, to enter the target cell, by interacting with the viral glycoprotein spikes. However, the complexity began when numerous studies identified the protective response of ACE2 in abbreviating the harmful effects of vasoconstrictor, anti-inflammatory peptide, angiotensin 2, by mediating its conversion to angiotensin-(1-7), which exercised antagonistic actions to angiotensin 2. Furthermore, certain investigations revealed greater resistance among children as compared to the geriatrics, towards COVID-19 infection, despite the elevated expression of ACE2 in pediatric population. Based upon such evidences, the review demonstrated possible therapeutic interventions, targeting both the protective and deleterious effects of ACE2 in COVID-19 disease, primarily inhibiting ACE2-virus interactions or administering soluble ACE2. Thus, the authors aim to provide an opportunity for the researchers to consider RAAS system to be a significant element in development of suitable treatment regime for COVID-19 pandemic.

Keywords: ACE2; Angiotensin 2; Angiotensin-(1–7); Corona virus; Glycoprotein spikes; RAAS system.

Graphical abstract

Fig. 1

Renin angiotensin system enzymatic cascade depicting primary receptor systems, biological actions of Angiotensin 2 and Ang-(1–7) and balance between ACE and ACE2. a) RAS system demonstrating metabolic pathway of angiotensin peptide, as an initiator compound, cleaved to form Ang 1, by renin (kidney). This is followed by cleavage of Ang 1 to Ang 2, by ACE, followed by ACE2 mediated cleavage of Ang 2 to Ang-(1–7). Ang 2 acts on AT1 and AT2 receptors, while Ang-(1–7) acts on Mas receptors, and antagonizes the actions of Ang 2/AT1R axis. b) Curbed levels of ACE2 results in shifting of balance, in the RAS, towards Ang 2/AT1R axis (activator), facilitating infection progression. Enhanced ACE2 levels, by rhACE2, ACE2 activators or gene therapy, shifts the balance towards Ang-(1–7)/MasR axis (inhibitor), resulting in protection from the viral infection.

Fig. 2

Entry mechanism and life cycle of SARS-CoV-2 in host cells. The glycoprotein spikes of the virus bind to its receptor human angiotensin converting enzyme (ACE2), through receptor-binding domain (RBD), proteolytically activated by human proteases, and enters the cell through endosomal pathway. This is followed by uncovering of viral RNA in the cytoplasm and translation of ORF1a and ORF1ab to produce pp1a and pp1ab polyproteins. These proteins are cleaved by RTC proteases, which facilitate the production of full length (−) RNA copies and serve as templates for full length (+) RNA genomes. A set of sub-genomic RNAs (sgRNAs) is produced via fragmented transcription, having numerous open reading frames (ORFs), where only the closest (5′ end) is translated. The nucleocaspids are mustered in the cytoplasm, after the production of viral structural proteins. This is followed by budding in the lumen of intermediate compartment of endoplasmic reticulum (ER) and golgi apparatus (ERGIC). This is followed by exocytosis mediated release of virion from the infected cell.

Fig. 3

Synergistic role of vitamin D and melatonin in mediating anti-inflammatory, antioxidant and anti-apoptotic actions, as well as preventing immune cell infiltration in mitigating COVID-19 infection. The solid lines indicate stimulatory, while the dashed lines indicate inhibitory actions; [MMP = matrix metalloproteinases, NLPR3 = nod like receptor protein-3, COX-2 = cyclooxygenase-2, VEGF = vascular endothelial growth factor, NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells, CRP = C-reactive protein, TLR4 = toll-like receptor 4, HMGB1 = high mobility group box 1, HSP70e/i = heat shock protein 70e/i, PD-1 = programmed cell death protein 1, IL-8/6/4/10/1β = interleukin-8/6/4/10/1β, INF-1 = interferon-1, iNOS = inducible nitric oxide synthase, CXCL = chemokine (C-X-C motif) ligand, TNF-α = tumor necrosis factor-alpha, RANTES = regulated on activation, normal T cell expressed and secreted, IgE = immunoglobulin E, TGF-β1 = transforming growth factor-β1, SIRT1 = sirtuin 1, NO = nitric oxide, MDA = malondialdehyde, +OH = hydroxide, GSH = glutathione, SOD = superoxide dismutase, G6PD = glucose-6-phosphate dehydrogenase, Nrf2 = nuclear factor erythroid 2-related factor 2, CASP3/1 = caspase 3/1, AIF = apoptosis-inducing factor, p38 = p38 mitogen activated protein kinases, JNK = c-Jun N-terminal kinases, Bax/Bcl-2/Bad = Bcl-2 family of apoptotic proteins].