“Decreased ACE 2 activity is a risk factor for severity/lethality of COVID-19”

The patient’s immune response seems to be the most important factor influencing the course of COVID-19. SARS-CoV uses several strategies to escape or suppress non-specific immune response. Comparison of patients who succumbed to SARS with survivors showed that the development of an adaptive immune response was a crucial factor. Specifically, the synthesis of antibodies against the spike protein of SARS-CoV.69 However, more detailed immunopathological analysis is beyond the scope of this paper.

Decreased activity of ACE 2 in high-risk comorbidities

Risk factors correlating positively with severity of COVID-19 have been described as higher age, male sex, hypertension, diabetes and cardiovascular diseases.70,71 Associations between some of these factors and the change of ACE 2 expression/activity may be found in the literature. Patients with heart failure have been reported to have upregulated expression of both ACE 2 mRNA and protein in cardiac tissue.72,73 However, there is also a study which failed to find differences in the expression of ACE 2 protein in the cardiac tissue between heart failure patients and healthy individuals.5 In animal models, ACE 2 deficiency is named as a risk factor worsening cardiac pathogenesis.6,73 In patients with hypertension, decreased vascular expression of ACE 2 may be expected, but ACE 2 activity in the CNS also plays an important role in the pathogenesis of hypertension.6,73 Also diabetes mellitus is associated with the reduction of ACE 2 activity 15,73. There are studies reporting decreased expression of renal ACE 2 protein in patients with diabetic nephropathy compared to healthy control.74 On the other hand, Lely et al.75 failed to find difference in the renal expression of ACE 2 protein in healthy individuals and patients with renal damage, including diabetic nephropathy. A study in rats showed correlation between higher age and decreased ACE 2 protein expression. This decrease was more pronounced in males76. However, there are studies which do not show any age-related changes of ACE 2 activity in rats77 and people78 with ARDS. Non-coherent transcriptome analyses stated in the section 2.1.3 do not provide a clear conclusion either.
Therefore, there are data supporting the theory that some risk factors of COVID-19 severity correlate with lower baseline expression/activity of ACE 2. And several authors are in favour of this theory.52,79,80 On the other hand, the data not fully compliant with this theory calls for caution. It is also important to mention that several comorbidities, e.g. diabetes, older age, and cardiovascular diseases, are negative prognostic factors in infectious diseases with a different pathogenesis than that of COVID-19 as well.81

Benefit of increasing ACE 2 activity

In addition to the patient’s adaptive immune response, the survival of COVID-19 requires maintained ACE 2 activity to avoid the development of fatal ARDS, as stated above. During ARDS caused by SARS-Cov-2, ACE 2 activity in AT 2 is likely to be substantially reduced, and it is therefore appropriate to restore it. The logical solution seems to be the infusion of recombinant ACE 2 protein. In COVID-19, serum ACE 2 protein can bind circulating SARS-CoV-2 and suppress virus replication, in addition to reducing the unfavourable ANG II/ANG (1-7) ratio. 19,82,83 From this point of view an inhalation form of an ACE 2 analogue would be interesting because of possible reduction of the viral load in the airways. The safety of recombinant ACE 2 has been demonstrated in pilot clinical trials in humans.8,19 It can therefore be expected for results of valid clinical trials in patients with COVID-19 to be shown in the near future.
Protective effect in ARDS may be expected from the administration of ANG (1-7) as a product of ACE 2.84,85 A study wherein high doses of calcitriol alleviated reduction of ACE 2 mRNA and protein expression during acute lung injury in mice seems to also be of interest.86 To provide a complete picture, calcitriol itself has not significantly increased natural expression of ACE 2 mRNA and protein in control group.
Some authors87,88 hypothesise a beneficial effect of AT1 R blockers in the treatment of COVID-19 patients. They speculate that AT1 R antagonism decreases harmful effects of ANG II. Furthermore, increase of circulating ANG II as an ACE 2 substrate will lead to quicker conversion to ANG (1-7). Consequently, Gurwitz assumes upregulation of ACE 2 expression.88 There is evidence supporting this hypothesis in ARDS conditions85 and very limited population-based data associating treatment with AT1 R blockers as a protective factor of COVID-19 severity.63,64 But clear and general effect of AT1 R blockers on the increase in ACE 2 expression in humans is not confirmed,55,59 as noted in section 2.2.1.
The currently available evidence supports the attempts to maintain ACE 2 activity in patients with severe COVID-19 as a life-saving strategy. It also seems rational to avoid increasing ACE 2 activity by its expression in the cells potentiating the replication cycle of SARS-CoV-2, e.g. AT 2. Further, a speculation on the use of direct ACE 2 activators: there have been several studies supporting the use of 1-[[2-(dimethylamino) ethyl] amino]-4-(hydroxymethyl)-7-[[(4-methylphenyl) sulfonyl] oxy] -9H-xanthone-9 (XNT) and diminazene aceturate (DIZE) in tissue and animal models, where ACE 2 activation increased ANG (1-7) and simultaneously decreased ANG II. 7,89 Unfortunately, their toxicity is not known. Therefore, their introduction into the clinical practice during the current COVID-19 pandemics is not plausible, but they indicate a possible direction of development.