Agonism of receptors activated by ACE2-derived peptides
Ang (1-7) is considered the major ACE2-derived peptide but ACE2 can also
generate other peptides, including Ang (1-9) and the heptapeptide
alamandine. Ang (1-7) primarily acts via the Mas-1 receptor
(Figure 2 ) while response to Ang (1-9) may also involve AT2R;
alamandine has effects similar to Ang (1-7) via interactions with the
Mas-related GPCR, member D (MrgD) (Alexander at al., 2019). The actions
of the ACE2-Ang (1-7)-Mas-1 receptor, ACE2-Ang (1-9)-AGTR2 and
ACE2-alamandine-MrgD pathways generally oppose those of the Ang II-AGRT1
pathway, though this remains controversial for AGTR2, as discussed
earlier in this text. Activation of the former pathways, in particular
via GPCRs that mediate their effects, is thus predicted to blunt
COVID-19 pathobiology. Signaling by ANG (1-7) via Mas-1 can increase
activity of MAP kinase, phosphoinositide 3-kinase/Akt and NADPH oxidase
and subsequently activate effectors that include forkhead box protein 01
(FOXO1), cyclcooxygenase 2 (COX2) and generation of prostanoids and
nitric oxide (NO) (Santos et al., 2019; Povlsen et al., 2020). Less is
currently known regarding alamandine signaling and action. Additional
peptides may be generated as part of non-canonical (“non-classic”) Ang
II signaling (Santos et al, 2019), Efforts are underway to discover and
develop drugs that mimic the physiological peptides in their actions on
Mas-1 and Mrgd receptors. Initial clinical studies have tested an oral
formulation of hydroxypropyl-β-cyclodextrin-ANG-(1−7) on muscle injury
(Becker et al., 2018). As recently reviewed (Wang et al., 2019),
targeting of non-canonical Ang signaling pathways has also been
initiated in studies of ARDS. Such approaches should be highly suitable
for testing in patients with COVID-19.