Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19

Abstract

Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.

An engineered ACE2 decoy receptor can be administered by inhalation and potently targets the BA.1 and BA.2 omicron variants of SARS-CoV-2

“…S binds to angiotensin-converting enzyme 2 (ACE2), which is highly expressed on type II alveolar lung epithelium (Hamming et al , 2004; Zhao et al , 2020), triggering conformational changes that facilitate fusion of the viral envelope and host cell membrane (Huang et al , 2020). ACE2 is a protease of the renin-angiotensin-aldosterone system (RAAS), which catalyzes the cleavage and inactivation of the vasoconstrictor angiotensin II (Ang-II) (Vickers et al , 2002; Tipnis et al , 2000), as well as the cleavage of other pro-inflammatory peptides in the kinin system that promote vascular leakage (Vickers et al , 2002), and formation of Ang 1-7 to mediate anti-inflammation, anti-fibrosis, and vasodilation through Mas signaling (Kuba et al , 2021; Santos et al , 2003). The extracellular domains of ACE2 can be expressed as a soluble protein (sACE2) that blocks the RBD (Hofmann et al , 2004).…”

Engineering ACE2 decoy receptors to combat viral escapability

“…Since increased Ang II and imbalance between AT1R and Mas receptor signals are involved in the pathogenesis of ARDS, ACE2 which converts Ang II to Ang 1–7, is expected to resolve this imbalance and improve lung inflammatory injury [ 29 , 30 ]. Indeed, the development of rhACE2 was motivated by its therapeutic effect in animal models of ARDS [ 31 ]. In clinical studies, although rhACE2 was well-tolerated in both healthy human volunteers and ARDS patients, and treatment resulted in rapid conversion of Ang II to Ang 1–7, no beneficial changes in acute physiology or clinical outcomes was detected [ 28 , 32 ].…”

“…Considering the therapeutic potential of rhACE2 for ARDS via conversion of proinflammatory Ang II to Ang 1–7, the enzymatic activity of the ACE2 decoy is expected to ameliorate lung inflammatory injury due to SARS-CoV-2 infection. Although there is extensive evidence to support the efficacy of rhACE2 in animal models of ARDS [ 30 , 31 ], Phase 2 trials have found no improvement in clinical outcomes of ventilated ARDS patients. It is possible that the dosage of rhACE2 may have been insufficient to show beneficial effects [ 30 ].…”

Cannabidiol and SARS-CoV-2 Infection

“…Moreover, the dysregulation in ACE2 expression in lung tissue may exacerbate outcomes in COVID-19 patients ( 70 ). In COVID-19 patients, ACE2 expression and the WNT/β-catenin pathway appeared to be interrelated ( 18 ).…”