Introduction:
Our previous studies have established that increasing the levels of pulmonary Angiotensin converting enzyme2 (ACE2) either by genetic overexpression or by a small molecule activator, Diminazene aceturate (DIZE) provides protection against lung injury. In view of the mounting evidence of the involvement of the gut microbiota in inflammatory, metabolic and neurological diseases, we proposed the following hypothesis: gut dysfunction and microbial dysbiosis is associated with pulmonary hypertension (PH) and that the cardiopulmonary beneficial effect of DIZE is mediated, in part, by its influence on the gut microbial composition.
Methods:
PH was induced in male Sprague Dawley rats by a single injection of monocrotaline (MCT; 50mg/Kg s.c). A subset of MCT rats was treated daily with DIZE (15mg/Kg/day s.c) for 4-weeks, after which hemodynamic parameters were measured and fecal samples collected for bacterial 16S ribosomal DNA analysis. In addition, colon samples were isolated to determine tissue stiffness by ex vivo atomic force microscopy.
Results:
MCT administration resulted in the development of PH as evidenced by increase in right ventricular systolic pressure (RVSP - Control: 30+2; MCT: 93+10 mmHg; p<0.05), which was associated with significant decreases in gut microbial richness (37%), diversity (22%), and evenness (16%). Furthermore, we observed a significant reduction in acetate- and butyrate-producing, and increases in lactate-producing bacterial population in PH animals. Elastic modulus and viscosity of the colon were increased by 61% and 86% respectively in MCT animals as compared with controls, indicating greater tissue stiffness (Elastic modulus - Control: 7.33+1.66; MCT: 11.84+3.41 kPa; Viscosity - Control: 145+19; MCT: 270+36 kPa*s; p<0.05). However, chronic treatment with DIZE attenuated all these parameters (RVSP - MCT+DIZE: 52+9 mmHg; Elastic modulus - MCT+DIZE: 8.97+3.84 kPa; Viscosity - MCT+DIZE: 180+77 kPa*s; p<0.05)
Conclusions:
These observations demonstrate for the first time that a) gut microbial dysbiosis is associated with MCT-induced PH; b) DIZE attenuates PH pathophysiology and significantly rebalances dysbiosis. They suggest that the gut microbiota could be a potential target for PH therapy.
Diminazene Aceturate Improves Autonomic Modulation in Pulmonary Hypertension