Diminazene, an ACE2 Activator Modulates Gut Microbiota and Provides Protection Against Pulmonary Hypertension

We have previously demonstrated that Diminazene aceturate (DIZE), an ACE2 activator attenuates pulmonary hypertension (PH). It is becoming clearer that disruption of the gut microbiome leads to metabolic and cardiovascular diseases. However, role of the gut microbiome in PH has not yet been studied. We hypothesized that PH is associated with microbial dysbiosis, and that treatment with DIZE restores the gut microbiome to provide cardiopulmonary protection. PH was induced in male Sprague Dawley rats by a single subcutaneous injection of monocrotaline (MCT, 50mg/Kg). A subset of MCT animals was treated daily with DIZE (15mg/kg, ip) for 4‐weeks, after which echocardiographic and hemodynamic measurements were performed, and fecal samples collected for microbiome analyses. MCT rats showed marked increase in right ventricular systolic pressure (RVSP; Control: 32 + 3 mmHg; MCT: 88 + 2 mmHg), along with the development of right ventricular hypertrophy (RVH; Control: 0.26 + 0.005; MCT: 0.61 + 0.01), which was associated with significant changes in the composition of the gut microbiota, and decreased levels of butyrate, a beneficial microbial metabolite. However, DIZE treatment restored the gut microbiome and increased butyrate levels to attenuate PH (RVSP; MCT+DIZE: 55 + 2mmHg) and associated cardiac hypertrophy (RVH; MCT+DIZE: 0.38+0.005). Collectively, our results demonstrate that PH is associated with microbial dysbiosis and that DIZE treatment modulates the gut microbiome to provide cardiopulmonary protection.