Induced dysregulation of ACE2 by SARS-CoV-2 plays a key role in COVID-19 severity

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of COVID-19, is reported to increase the rate of mortality worldwide. COVID-19 is associated with acute respiratory symptoms as well as blood coagulation in the vessels (thrombosis), heart attack and stroke. Given the requirement of angiotensin converting enzyme 2 (ACE2) receptor for SARS-CoV-2 entry into host cells, here we discuss how the downregulation of ACE2 in the COVID-19 patients and virus-induced shift in ACE2 catalytic equilibrium, change the concentrations of substrates such as angiotensin II, apelin-13, dynorphin-13, and products such as angiotensin (1-7), angiotensin (1-9), apelin-12, dynorphin-12 in the human body. Substrates accumulation ultimately induces inflammation, angiogenesis, thrombosis, neuronal and tissue damage while diminished products lead to the loss of the anti-inflammatory, anti-thrombotic and anti-angiogenic responses. In this review, we focus on the viral-induced imbalance between ACE2 substrates and products which exacerbates the severity of COVID-19. Considering the roadmap, we propose multiple therapeutic strategies aiming to rebalance the products of ACE2 and to ameliorate the symptoms of the disease.

Keywords: ACE2; Acute Respiratory Syndrome; Angiotensin; COVID-19; Cardiovascular Disease.

Graphical abstract

Fig. 1

Effects of Ang II on organs. ACE degrades Ang I and produces Ang II which binds to its receptors (ATRs). Then, ACE2 converts Ang II into Ang 1–7. SARS-CoV-2 downregulates the expression of ACE2 and causes the pathological symptoms in several human organs due to accumulation of Ang II (Created in BioRender.com). Ang I: angiotensin I, Ang II angiotensin II, Ang 1–7. angiotensin 1–7, ACE: angiotensin-converting enzyme, ACE2: angiotensin-converting enzyme2, AT1R: Angiotensin II receptor type 1, AT4R: Angiotensin II receptor type 4, PAI-1: Plasminogen activator inhibitor-1 ROS: Reactive Oxygen Species, VEGF: Vascular endothelial growth factor, ARB drugs: angiotensin II receptor blocker drugs, ACEi drugs: Angiotensin-converting enzyme inhibitor drugs, BBB: blood–brain barrier.

Fig. 2

Ang 1–7 functions in several organs. ACE2 converts Ang II into Ang 1–7 which acts through its receptors (MasR). SARS-CoV-2 downregulates the expression of ACE2 and reduces the concentration of Ang 1–7 leading to progressive deterioration of physiological functions in patients with COVID-19 (Created in BioRender.com). ACE2: angiotensin converting enzyme2, Ang 1–9: Angiotensin 1–9, Ang 1–7: Angiotensin 1–7, MasR: mitochondrial assembly receptor, TGF-β: Transforming growth factor beta.

Fig. 3

Ang 1–9 functions in human organs. ACE2 converts Ang1 to the Ang 1–9 and the latter acts through its receptor (AT2R). SARS-CoV-2 downregulates the expression of ACE2 which ultimately reduces the concentration of Ang 1–9. The decrease in the concentration of Ang 1–9 results in the loss of its beneficial functions in several organs in patients with COVID-19 (Created in BioRender.com). ACE2: angiotensin converting enzyme2, Ang I: Angiotensin I, Ang 1–9: Angiotensin 1–9, AT₂R; Angiotensin II receptor type 2, MI: myocardial infarction, vWF: von Willebrand factor, α-SMA: α-smooth muscle actin.

Fig. 4

The binding of dynorphin-13 to κ-opioid and NMDA receptors. Dynorphin A (1–13) binds to κ-opioid receptor and NMDA-glutamatergic. ACE2 degrades dynorphin A 1–13 and subsequently produces dynorphin A 1–12. SARS-CoV-2 downregulates the expression of ACE2 and thus the harmful effects of dynorphin A 1–13 accumulation causes the loss of neurons via NMDA receptor (Created in BioRender.com). PKC: Protein kinase C, NO: nitric oxide, cAMP: Cyclic Adenosine Monophosphate, NMDA: N-Methyl-D-aspartic acid.

Fig. 5

Schematic presentation of the interactions among the immune system and ACE2 substrates and products (Created in BioRender.com). ACE2: Angiotensin converting enzyme2, Ang I: Angiotensin I, Ang II: Angiotensin II, Ang 1–9: Angiotensin 1–9, Ang 1–7. Angiotensin 1–7, AT1R; Angiotensin II receptor type 1, AT2R; Angiotensin II receptor type 2, MAS R: Mas receptor, APJ: Apelin receptor, ROS: Reactive Oxygen Species, ERK1/2: Extracellular signal-regulated kinases, MAPK: Mitogen-activated protein kinase, PI3K: Phosphatidylinositol-3-kinase, PKC: Protein kinase C, Th1: T helper cell 1, Th0: Naive T cell, NF-κB: Nuclear factor-κB, AP-1: Activator protein 1, ABCA1-p: ATP binding cassette transporter A1- phosphorylated.