Abstract 037: Global ACE2 Over-Expression is Protective Against a Dysfunctional Brain-Gut-Lung Axis in Hypoxia-Induced Pulmonary Hypertension

Background and Objectives: Angiotensin converting enzyme 2 (ACE2), key enzyme of the vasoprotective axis of the renin angiotensin system, has been implicated in many pulmonary diseases including pulmonary hypertension (PH). Plasma levels of ACE2 in group-1 pulmonary hypertensive patients are decreased and activation of this enzyme by small molecule activators, overexpression or administration of recombinant ACE2, all have beneficial outcomes on PH. Furthermore, involvement of neuroinflammation and impaired brain-gut-lung axis have been proposed in PH. These observations have led us to propose that beneficial effect of ACE2 are, at least in part, due to attenuation of neuroinflammation and rebalancing of gut microbiota and improvement in pathology. Methods: ACE2 knock-in (ACE2KI) and wild-type mice (WT; C57BL/6) were subjected to hypoxia (10% FIO2) or room air for 4 weeks (n=8-10/group). Right ventricular systolic pressure (RVSP), and electrocardiography were performed, tissues examined by standard histological techniques, and stool collected for 16S rRNA analysis at 4 weeks. Results: Hypoxia-induced significantly increased RVSP in WT but not ACE2KI mice (20±1.6 vs 32±1.9, p<0.001 and 24.3±1.5 vs 21±1.3mmHg, respectively). This was accompanied in WT, but not ACEKI, by ~5-fold increase in sympathetic activation (LF/HF; p<0.001) and ~2-fold increase (p<0.01) in microglia activation in the paraventricular nucleus (PVN) of the hypothalamus. There was increased fibrotic area (p<0.01) and muscularis layer thickening (p<0.001) and decreased villi length (p<0.01) and goblet cells (p<0.001) in the small intestine of WT but not ACE2KI mice following hypoxia. Finally, beta diversity of gut microbiome of WT, but not ACE2KI, mice was significantly altered by hypoxia (ANOSIM P=0.001). Conclusions: Microglial activation in PVN, sympathetic activation, gut pathology and altered gut microbiome are associated with hypoxia-induced PH. Global overexpression of ACE2 prevents all of these parameters. The involvement of organs other than lungs, and ACE2, present novel therapeutic potentials for PH.