吴茱萸次碱抑制大鼠球囊损伤动脉模型中的内膜增生
Rutaecarpine Inhibits Intimal Hyperplasia in A Balloon-Injured Rat Artery Model.
作者信息
Xu Yang, Chen Xiu-Ping, Zhang Feng, Hou Hua-Hua, Zhang Jing-Yi, Lin Shu-Xian, Sun An-Sheng
机构信息
Key Laboratory of Basic Pharmacology of Guizhou and Department of Pharmacology, Zunyi Medical College, Zunyi, Guizhou Province, 563099, China.
Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.
出版信息
Chin J Integr Med. 2018 Jun;24(6):429-435. doi: 10.1007/s11655-017-2900-3. Epub 2017 Sep 1.
OBJECTIVE
To investigate the effect and potential mechanisms of rutaecarpine (Rut) in a rat artery balloon-injury model.
METHODS
The intimal hyperplasia model was established by rubbing the endothelia with a balloon catheter in the common carotid artery (CCA) of rats. Fifty rats were randomly divided into five groups, ie. sham, model, Rut (25, 50 and 75 mg/kg) with 10 rats of each group. The rats were treated with or without Rut (25, 50, 75 mg/kg) by intragastric administration for 14 consecutive days following injury. The morphological changes of the intima were evaluated by hematoxylin-eosin staining. The expressions of proliferating cell nuclear antigen (PCNA) and smooth muscle (SM) α-actin in the ateries were assayed by immunohistochemical staining. The mRNA expressions of c-myc, extracellular signal-regulated kinase 2 (ERK2), MAPK phosphatase-1 (MKP-1) and endothelial nitric oxide synthase (eNOS) were determined by real-time reverse transcription-polymerase chain reaction. The protein expressions of MKP-1 and phosphorylated ERK2 (p-ERK2) were examined by Western blotting. The plasma contents of nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP) were also determined.
RESULTS
Compared with the model group, Rut treatment significantly decreased intimal thickening and ameliorated endothelial injury (P<0.05 or P<0.01). The positive expression rate of PCNA was decreased, while the expression rate of SM α-actin obviously increased in the vascular wall after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01). Furthermore, the mRNA expressions of c-myc, ERK2 and PCNA were downregulated while the expressions of eNOS and MKP-1 were upregulated (P<0.05 or P<0.01). The protein expressions of MKP-1 and the phosphorylation of ERK2 were upregulated and downregulated after Rut (50 and 75 mg/kg) administration (P<0.05 or P<0.01), respectively. In addition, Rut dramatically reversed balloon injury-induced decrease of NO and cGMP in the plasma (P<0.05 or P<0.01).
CONCLUSION
Rut could inhibit the balloon injury-induced carotid intimal hyperplasia in rats, possibly mediated by promotion of NO production and inhibiting ERK2 signal transduction pathways.
目的
研究吴茱萸次碱（Rut）在大鼠动脉球囊损伤模型中的作用及潜在机制。
方法
采用球囊导管摩擦大鼠颈总动脉（CCA）内皮建立内膜增生模型。50只大鼠随机分为5组，即假手术组、模型组、Rut（25、50和75 mg/kg）组，每组10只。损伤后连续14天经胃内给予或不给予Rut（25、50、75 mg/kg）。通过苏木精-伊红染色评估内膜的形态学变化。采用免疫组织化学染色检测动脉中增殖细胞核抗原（PCNA）和平滑肌（SM）α-肌动蛋白的表达。通过实时逆转录-聚合酶链反应测定c-myc、细胞外信号调节激酶2（ERK2）、丝裂原活化蛋白激酶磷酸酶-1（MKP-1）和内皮型一氧化氮合酶（eNOS）的mRNA表达。通过蛋白质印迹法检测MKP-1和磷酸化ERK2（p-ERK2）的蛋白表达。还测定了血浆中一氧化氮（NO）和环磷酸鸟苷（cGMP）的含量。
结果
与模型组相比，Rut治疗显著降低内膜增厚并改善内皮损伤（P<0.05或P<0.01）。给予Rut（50和75 mg/kg）后，PCNA阳性表达率降低，而血管壁中SMα-肌动蛋白表达率明显升高（P<0.05或P<0.01）。此外，c-myc、ERK2和PCNA的mRNA表达下调，而eNOS和MKP-1的表达上调（P<0.05或P<0.01）。给予Rut（50和75 mg/kg）后，MKP-1的蛋白表达上调，ERK2的磷酸化下调（分别为P<0.05或P<0.01）。此外，Rut显著逆转了球囊损伤诱导的血浆中NO和cGMP的降低（P<0.05或P<0.01）。
结论
Rut可抑制大鼠球囊损伤诱导的颈动脉内膜增生，可能是通过促进NO生成和抑制ERK2信号转导通路介导的。
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