Session Type: Abstract Submissions (ACR)
Background/Purpose: Angiotensin-converting enzyme 2 (ACE2) is a member of renin-angiotensin system that plays a critical role in regulating blood pressure and cardiovascular function. It is a homologue of ACE and converts angiotensin (Ang) II into Ang-(1-7), which has the vasoprotective effects. Recent studies have demonstrated the therapeutic effects of ACE2 activation by a synthetic molecule or by forced expression of ace2 cDNA in experimental pulmonary hypertension models. We recently reported that inhibitory anti-ACE2 antibodies were detected in patients with autoimmune diseases (AID) with constrictive vasculopathy, pulmonary arterial hypertension, or persistent digital ischemia. We investigate whether 1-[(2-dimethylamino) ethylamino]-4 (hydroxymethyl)-7- [(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one (XNT), ACE2 activator identified by Ferreria et. al.1) overcomes on the inhibitory effect of anti-ACE2 antibodies in AID patients.
Methods: Immunoglobulin G was purified from sera of 13 vasculopathy and 11 non-vasculopathy patients with protein G sepharose beads. To evaluate the inhibitory effect against ACE2 by anti-ACE2 antibodies, we performed the measurement of ACE2 activity. ACE2 activity was monitored with fluorescent substrate following pre-treatment of ACE2 and purified IgG. Moreover, the interacting alternation of between ACE2 and IgG by XNT was examined by ELISA and western blot analysis.
Results: ACE2 activity was reduced by IgG purified from sera of 12 of 13 AID patients (92.3 %) with vasculopathy, but not that of 10 of 11 non-vasculopathy patients (90.9 %) and healthy subjects. Furthermore, in 2 of 12 samples retained ACE2 inhibitory effects, XNT overcame the inhibitory effects when added to IgG-ACE2 complex mixture. Moreover, XNT cancelled the binding of anti-ACE2 to ACE2.
Conclusion: The ACE2 activator, XNT increased ACE2 activity suppressed by IgG of AID patients. Our results suggested that XNT cancelled antigen-antibody reaction inducing a dynamic conformation change of ACE2. We propose that it is important to identify the activator which has the inducible capability of structural change against ACE2 and such compound is sufficiently expectable as candidate of therapeutic agent.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-small-molecule-activator-to-ace2-prevents-the-inhibition-of-ace2-activity-by-autoantibodies/