5.2 Rebalancing the RAAS axes by rhACE2
SARS-CoV-2 infection reduced ACE2 activity and increased the receptor consumption, further exacerbating pathophysiological changes, such as ACE/ACE2 ratio imbalance. Accordingly, there are several potential approaches to address ACE2-mediated COVID-19, including increases the expression and the activity of ACE2 to regulate the imbalance of RAAS. The imbalance of RAAS may result in abnormal high blood pressure and further induce multiple organ damage. Activation of the ACE2/Ang (1-7)/MasR signaling pathway or inhibition of the ACE/Ang Ⅱ/AT1R pathway may be alternative treatments for novel coronavirus. Treatment with rhACE2 is the direct approach to regulate the ACE2/Ang (1-7)/MasR axis. A few pilot clinical studies have been conducted using rhACE2 in ARDS, and sepsis. For example, Monteil found that clinical grade recombinant human soluble ACE2 can significantly block early stages of SARS-CoV-2 infections(Monteil et al. , 2020). In a pilot clinical trial (NCT01597635)(Khan et al. , 2017), patients with ARDS treated with rhACE2 exhibited decreased plasma Ang Ⅱ and elevated plasma Ang (1-7). An additional pilot study (NCT101884051) investigated the effects of rhACE2 in pulmonary arterial hypertension which is found that the ACE2 activity reduced(Hemnes et al. , 2018). The pharmacokinetics and pharmacodynamics of soluble rhACE2 treatment in healthy volunteers showed increased Ang (1-7) with no effect on blood pressure and heart rate (NCT00886353)(Haschke et al. , 2013). These clinical trials showed treatment with rhACE2 may improve excessive inflammation via activation of the ACE2/Ang (1-7)/Mas signaling pathway. Interestingly, treatment with rhACE2 may be completed with SARS-Cov-2 for ACE2, thus reduced the susceptibility of ACE2 binding to the virus.