Maybe, hopefully if I looked at this tomorrow, I would wonder why I was so feeble-minded today. But today anyway, I am confused.

Relative to COVID, we have been talking about decreasing ACE2 levels as potentially therapeutic, have we not?   

 - - -

"ACE2 is a cell surface receptor used by 2019-nCoV to gain entry into host cells. Apabetalone reduces circulating ACE2 protein levels in patients, and downregulates ACE2 gene transcription by 40-90% in vitro •Phase 2 trial planned"  (slide 37 of recent talk)

 And

https://www.sciencedirect.com/science/article/pii/S2352340916304838?via%3Dihub and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990638/  (Same article, see Table 3)

BUT See

 https://cardiacrhythmnews.com/decreased-ace2-levels-found-in-cardiovascular-disease-can-increase-likelihood-of-severe-covid-19/

“compared with young individuals, older persons with CVD who already have reduced ACE2 levels will be expected to be more predisposed to exaggerated inflammation with further reduction in ACE2 expression in the context of COVID-19, manifesting with greater disease severity.”

https://www.sciencedirect.com/science/article/pii/S002432052030655X

Thus, the downregulation of ACE2 during SARS-CoV-2 infection decreases the lung's ability to recover from the acute injury and may cause severe pneumonia lung failure, as clinically observed, see Fig. 2.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.15016

 "...Another novel approach addresses the peptidaseACE2whichconverts the peptide hormonesangiotensin Iandangiotensin IItotheir vasodilator derivates (angiotensin-(1–9)andangiotensin-(1–7),respectively) with a preference for angiotensin II degradation. How-ever, ACE2 may also degrade other vasodilatory factors such asapelin(see below; Kazemi-Bajestani, Patel, Wang, & Oudit, 2012).Decreased  ACE2  levels  and  ACE2  autoantibodies  have  beenreported in PAH (Tan, Liao, Zhou, Mei, & Wong, 2018). An open-label pilot study on acute haemodynamic responses after a singleinfusion of recombinant human ACE2 in patients with PAH showedimproved CO without a significant change in mPAP or systemicpressures, and reduced markers of oxidant and inflammatory stress(Hemnes et al., 2018). A dose-escalation study in PAH is currentlyrecruiting patients (ClinicalTrials.gov identifier: NCT03177603"  Note:– Trial completed and GSK dropped this drug after the trial -but still... ?

Do we actually want to reduce ACE2 or increase it?