枯茗醇和槲皮素通过 PARP1 介导的 miR-204 下调及其下游通路改善野百合碱诱导的大鼠肺动脉高压。
Perillyle alcohol and Quercetin ameliorate monocrotaline-induced pulmonary artery hypertension in rats through PARP1-mediated miR-204 down-regulation and its downstream pathway.
机构信息
PhD candidate, Department of Physiology and Pharmacology, and Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Science, Kerman, Iran.
出版信息
BMC Complement Med Ther. 2020 Jul 13;20(1):218. doi: 10.1186/s12906-020-03015-1.
BACKGROUND
Pulmonary 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.
METHODS
Thirty 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.
RESULTS
Inflammation 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.
CONCLUSION
PA 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.
背景
肺动脉高压（PAH）是一种肺部血管疾病，其特征为肺动脉压升高（PAP）。许多 microRNA 在 PAH 的病理生理学中发挥作用。紫苏醇（PA）和槲皮素（QS）是具有抗氧化和抗增殖特性的植物衍生化合物。我们研究了 PA 和 QS 对实验性 PAH 中 PAP、PARP1、miR-204 及其靶蛋白 HIF1α 和 NFATc2 表达的影响。
方法
30 只大鼠分为对照组、MCT 组、MCT+Veh 组、MCT+PA 组和 MCT+QS 组。MCT（60mg/kg）皮下注射诱导 PAH。PA（50mg/kg/d）和 QS（30mg/kg/d）在诱导 PAH 后 3 周给予。通过右心室插管、H&E 染色、实时 qPCR 和 Western blot 分别评估 PAP、肺病理学、miRNA 和 mRNA 的表达以及靶蛋白。
结果
与对照组相比，MCT 组的炎症和肺小动脉厚度增加。PA 和 QS 显著改善了炎症并显著减少了小动脉厚度。miR-204 在 PAH 大鼠中的表达降低（p<0.001）。PA（p<0.001）和 QS（p<0.01）显著增加了 miR-204 的表达。MCT+veh 大鼠中 PARP1、HIF1α、NFATc2 和α-SMA mRNA 的表达显著增加（均 p<0.001），用 PA 和 QS 治疗后降低（均 p<0.01）。PA 和 QS 还降低了在 MCT+Veh 组中增加的 PARP1、HIF1α 和 NFATc2 蛋白的表达。
结论
PA 和 QS 可能通过影响 PARP1 和 miR-204 及其下游靶标 HIF1a 和 NFATc2 的表达来改善 PAH。PA 和 QS 可能是治疗 PAH 的治疗目标。
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