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20 pages, 3418 KiB

Open AccessReview

Unraveling the Underlying Molecular Mechanism of ‘Silent Hypoxia’ in COVID-19 Patients Suggests a Central Role for Angiotensin II Modulation of the AT1R-Hypoxia-Inducible Factor Signaling Pathway

by Christian Albert Devaux and Jean-Christophe Lagier

J. Clin. Med. 2023, 12(6), 2445; https://doi.org/10.3390/jcm12062445 - 22 Mar 2023

Cited by 5 | Viewed by 3385

A few days after being infected with SARS-CoV-2, a fraction of people remain asymptomatic but suffer from a decrease in arterial oxygen saturation in the absence of apparent dyspnea. In light of our clinical investigation on the modulation of molecules belonging to the [...] Read more.

A few days after being infected with SARS-CoV-2, a fraction of people remain asymptomatic but suffer from a decrease in arterial oxygen saturation in the absence of apparent dyspnea. In light of our clinical investigation on the modulation of molecules belonging to the renin angiotensin system (RAS) in COVID-19 patients, we propose a model that explains ‘silent hypoxia’. The RAS imbalance caused by SARS-CoV-2 results in an accumulation of angiotensin 2 (Ang II), which activates the angiotensin 2 type 1 receptor (AT1R) and triggers a harmful cascade of intracellular signals leading to the nuclear translocation of the hypoxia-inducible factor (HIF)-1α. HIF-1α transactivates many genes including the angiotensin-converting enzyme 1 (ACE1), while at the same time, ACE2 is downregulated. A growing number of cells is maintained in a hypoxic condition that is self-sustained by the presence of the virus and the ACE1/ACE2 ratio imbalance. This is associated with a progressive worsening of the patient’s biological parameters including decreased oxygen saturation, without further clinical manifestations. When too many cells activate the Ang II-AT1R-HIF-1α axis, there is a ‘hypoxic spillover’, which marks the tipping point between ‘silent’ and symptomatic hypoxia in the patient. Immediate ventilation is required to prevent the ‘hypoxic spillover’. Full article

(This article belongs to the Collection Coronavirus Disease 2019: Clinical Presentation, Pathogenesis and Treatment)

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Figure 1

Figure 1
<p>Structure of the renin–angiotensin–(aldosterone) system and the role of ACE2 in this physiological system. ACE1 catalyzes the conversion of angiotensin I (Ang I) to angiotensin II (Ang II). ACE2 catalyzes the conversion of Ang I to angiotensin-(1-9) and the conversion of Ang II to angiotensin-(1-7). There are also known interactions between the RAS and the Kininogen–(kallikrein)–Bradykinin system (not shown). Under normal physiological conditions, ACE2 converts Ang II into Ang-(1-7), which exhibits vasodilatory, anti-proliferative, and anti-inflammatory effects via the G protein-coupled receptor called Mas-1. Ang-(1-7) counterbalances the vasoconstrictor and inflammatory effect of Ang II. Upon SARS-CoV-2 entry, the downregulation of ACE2 decreases its ability to generate angiotensin (1-9) from Ang I and angiotensin-(1-7) from Ang II, leading to renin–angiotensin system (RAS) imbalance and overactivation of the Ang II -AT1R axis. For more details, see reference [<a href="#B70-jcm-12-02445" class="html-bibr">70</a>].</p> Full article ">Figure 2
<p>Schematic diagram illustrating the dual regulation of HIF-1α. (<b>a</b>) At normal O<sub>2</sub> concentration, HIF-1α is hydroxylated by the prolyl hydroxylase (PHD). The ubiquitin ligase VHL targets HIF-1α-OH for polyubiquitinylation and proteosomal degradation. Similarly, hydroxylation of the transient receptor potential channel (TRP) by PHD, and asparaginyl hydroxylase FIH targeting TRP-OH for ubiquitinylation and proteosomal degradation, contribute to homeostasis. (<b>b</b>) Ang II can contribute to hypoxia through binding to AT1R, which initiates signaling events including activation of reactive oxygen species (ROS) by mitochondria. Under hypoxia, HIF-1α translocates to the cell nucleus where it forms heterodimers with the HIF-β subunit and binds to the hypoxia response element (HRE) in the promoter of hypoxia-inducible genes, recruiting histone acetyltransferases CREB Binding Protein (CBP)/p300 to modulate hypoxia-inducible genes expression. For more details, see reference [<a href="#B65-jcm-12-02445" class="html-bibr">65</a>].</p> Full article ">Figure 3
<p>Representative list of cellular genes upregulated by HIF-1. HIF-1α is considered a ‘master regulator’ type of transcription factor capable of controlling the expression of a multitude of genes grouped under the heading of hypoxia-inducible genes α (the list is not exhaustive and grows continuously). The consensus DNA sequence for HIF-1α/HIF-1β binding is common for many genes upregulated during hypoxia. It is worth noting that several genes involved in the RAS, in the development and functioning of the vascular system (which modulate vascular tone or promote angiogenesis), and in erythropoiesis, belong to this list.</p> Full article ">Figure 4
<p>Proposed model of signaling in SARS-CoV-2-induced silent hypoxia. In order to simplify the representation of the signaling pathways, the effects of Ang II have been summarized on a single cell, but several different cell types are involved in the process of ‘silent hypoxia’ and can therefore respond in a specific way to Ang II stimulation. When SARS-CoV-2 is present, the binding of SARS-CoV-2 to ACE2 leads to the dysfunction of ACE2, reduced hydrolysis of Ang II, and increased levels of Ang II. Under this condition, Ang-(1-7) is not sufficient to counterbalance the activity of Ang II. The binding of Ang II to the AT1R activates a signaling cascade that contributes to the lowering of intracellular oxygen and a reduction in the hydroxylation of HIF-1α by PHD. Under these conditions, HIF-1α translocates to the cell nucleus, forms heterodimers with the HIF-1α, and controls the expression of hypoxia-inducible genes. This leads to the upregulation of the ACE1 gene, which contributes to further increases in Ang II, the increased expression of TRPA1, and to the modulation of expression of various genes. In addition, chronic HIF triggers the downregulation of the ACE2 gene and the activation of ADAM17, which leads to the cleavage of the ACE2, the release of soluble ACE2 (sACE2), and S1/sACE2 complexes formation. Finally, there is a decrease in nitric oxide (NO) bioavailability, since O<sub>2</sub>- inactivates NO.</p> Full article ">Figure 5
<p>Physiologic mechanisms governing the control of breathing. Peripheral chemical and mechanical sensory receptors are involved in the control of breathing and the sensation of dyspnea. Peripheral chemoreceptors located in the aortic arch and the carotid arteries act as sensors for both O<sub>2</sub> tension and CO<sub>2</sub> tension. Pulmonary alveolar walls receptors include joint receptors and stretch receptors. Chemoreceptors in the central and peripheral airways act as irritant sensors. Mechanoreceptors located on the ribs provide information regarding displacement, while muscle tendons provide information regarding tension development. Muscle spindles provide integrated information. The central nervous system integrates these signals and governs breathing (neurons that regulate breathing are widely dispersed in the central cortex, the hypothalamus, the limbic/paralimbic system, pons, and medulla). In moderate hypoxemia, patients respond with intense cardiovascular response (e.g., increased tachycardia, cardiac output, and systemic arterial blood pressure) and accelerated breathing. In contrast, profound hypoxemia (SaO<sub>2</sub> below 50%) is associated with cardiovascular collapse that results in loss of consciousness, bradycardia, and shock. The ‘hypoxic spillover’ corresponds to sudden deterioration in both oxygen saturation and cardiovascular compensation. For more details, see reference [<a href="#B149-jcm-12-02445" class="html-bibr">149</a>].</p> Full article ">

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