Perillyl alcohol, quercetin, and berberine combination therapy ameliorates experimental pulmonary arterial hypertension: Effects on the lung miR-204 expression, remodeling, and inflammatory factors.

Objective: Pulmonary artery hypertension (PAH) is a devastating syndrome. Our previous studies showed that perillyl alcohol (P), berberine (B) and quercetin (Q) improve PAH. In this study, we investigated the effects of sub-effective doses of these derivatives in double and triple combination forms on PAH in rats. Materials and Methods: Forty nine rats were divided into seven groups (n=7): 1) control, 2) monocrotaline (MCT), 3) MCT+vehicle (veh), 4) MCT+BP, 5) MCT+PQ, 6) MCT+BQ, and 7) MCT+BPQ. After three weeks of PAH induction with MCT (60 mg/kg), either vehicle (ethanol 5% in saline) or one of the above combinations (dose of 20 mg/kg for B, and doses of 20 and 10 mg/ kg for P and Q in vehicle) was administered for three weeks. Right ventricular (RV) pressure, contractility indices, lung pathology, miR-204 expression, oxidative stress markers, inflammation and apoptosis were assayed. Results: MCT increased RV systolic pressure and hypertrophy, and lung arteriole wall thickness, fibrosis and leukocyte infiltration in the MCT group compared to the CTL group. All treatments improved these effects significantly. Furthermore, MCT reduced antioxidant factors, Bax, P21 and miR-204 expression and increased Tumor Necrosis Factor alpha (TNF-α), Interleukin 6 (IL-6) and Bcl-2. All of these effects were recovered by combination treatments. Conclusion: The results showed that combination therapy with sub-effective/ineffective doses of these compounds had ameliorative effects against PAH.