Abstract
BackgroundPulmonary artery hypertension (PAH) is a vascular disease in the lung characterized by elevated pulmonary arterial pressure (PAP). Many miRNAs play a role in the pathophysiology of PAH. Perillyle alcohol (PA) and Quercetin (QS) are plant derivatives with antioxidant and anti-proliferative properties. We investigated the effect of PA and QS on PAP, expression of PARP1, miR-204, and their targets, HIF1α and NFATc2, in experimental PAH.MethodsThirty rats were divided into control, MCT, MCT + Veh, MCT + PA and MCT + QS groups. MCT (60 mg/kg) was injected subcutaneously to induce PAH. PA (50 mg/kg daily) and QS (30 mg/kg daily) were administered for 3 weeks after inducing PAH. PAP, lung pathology, expression of miRNA and mRNA, and target proteins were evaluated through right ventricle cannulation, H&E staining, real-time qPCR, and western blotting, respectively.ResultsInflammation and lung arteriole thickness in the MCT group increased compared to control group. PA and QS ameliorated inflammation and reduced arteriole thickness significantly. miR-204 expression decreased in PAH rats (p < 0.001). PA (p < 0.001) and QS (p < 0.01) significantly increased miR-204 expression. Expression of PARP1, HIF1α, NFATc2, and α-SMA mRNA increased significantly in MCT + veh rats (all p < 0.001), and these were reduced after treatment with PA and QS (both p < 0.01). PA and QS also decreased the expression of PARP1, HIF1α, and NFATc2 proteins that had increased in MCT + Veh group.ConclusionPA and QS improved PAH possibly by affecting the expression of PARP1 and miR-204 and their downstream targets, HIF1a and NFATc2. PA and QS may be therapeutic goals in the treatment of PAH.
Highlights
Pulmonary artery hypertension (PAH) is a vascular disease in the lung characterized by elevated pulmonary arterial pressure (PAP)
Determining optimum doses of Perillyle alcohol (PA) and QS To determine the optimum doses of PA and QS in treatment of PAH, after induction of the disease, a pilot dose-response study was performed using different doses of these plant derivatives (Fig. 1)
In this study, we investigated the effect of PA and QS on miR-204 expression and its downstream protein targets in rat lungs affected by MCT-induced PAH
Summary
Pulmonary artery hypertension (PAH) is a vascular disease in the lung characterized by elevated pulmonary arterial pressure (PAP). Pulmonary artery hypertension (PAH) is a chronic disease of the pulmonary vasculature characterized by elevated pulmonary arterial pressure (PAP) due to remodeling and vasoconstriction in small arterioles, leading to right ventricular failure and death [1, 2]. Efforts are ongoing to understand the molecular pathways and mechanisms involved in the pathophysiology of PAH and finding more effective therapies. Micro-RNAs (miRNAs) are small non-coding RNAs that are dysregulated in many diseases [4, 5] These small single-stranded RNAs are about 22 nucleotides in length and destroy/suppress translation of their target mRNAs by binding to them, thereby affecting the expression of the target genes [5]. In a study on colorectal cancer, miR-204 suppressed tumor cell proliferation and invasion and increased the susceptibility of the cells to chemical treatments [10]
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