Perillyl alcohol and quercetin modulate the expression of non-coding RNAs MIAT, H19, miR-29a, and miR-33a in pulmonary artery hypertension in rats

BACKGROUND: Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play critical roles in the pathogenesis and progression of pulmonary artery hypertension (PAH). LncRNA H19, myocardial infarction-associated transcript (MIAT), miR-29a, and miR-33a have been suggested as potential targets for treating arterial hypertension. We explored the expression pattern of non-coding RNAs H19, MIAT, miR-29a, and miR-33a in monocrotaline (MCT)-induced PAH rats. Moreover, we investigated whether perillyl alcohol (PA) and quercetin (QS), two plant derivatives with beneficial effects on PAH-induced abnormalities, act through regulating the expression of these non-coding RNAs. METHODS: Male Wistar rats (n = 30) were divided into five groups. MCT (60 mg/kg) was injected subcutaneously to induce PAH. PA (50 mg/kg daily) and QS (30 mg/kg daily) were administered three weeks after induction of PAH. H&E staining and qRT-PCR were performed to assess arteriole wall thickness and gene expression, respectively. RESULTS: Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) increased in MCT and MCT + Veh. groups compared to the control group (in both P < 0.001). QS and PA decreased RVSP and RVH significantly. Wall thickness and fibrosis score in the MCT group (score 3) increased compared to the control group (score 0). PA and QS ameliorated wall thickness and fibrosis to score 1 (mild). Also, the expression of miR-29a and miR-33a decreased in the PAH group (in both, P < 0.001). Treatment with PA and QS decreased the expression of H19 (P < 0.001) and MIAT (P < 0.01) and increased the expression of miR-29a (P < 0.01) and miR-33a significantly (P < 0.05 for QS and P < 0.001 for PA). CONCLUSIONS: The beneficial effects of PA and QS on PAH-induced abnormalities were exerted through returning the dysregulated expression of H19, MIAT, miR-29a, and miR-33a to normal levels in rats with MTC-induced PAH. This study emphasized the therapeutic potential of PA and QS in PAH. However, more detailed investigations are needed to clarify the underlying molecular mechanisms.