摘要
目的研究埃克替尼对野百合碱(MCT)诱导的肺动脉高压(PH)大鼠右心室重构的影响。方法将SD大鼠随机分为对照组(0.3%羧甲基纤维素钠)、模型组和低、高剂量实验组(30、60 mg·kg^(-1)埃克替尼),每组8只。模型组和低、高剂量实验组单次腹腔注射60 mg·kg^(-1)MCT建立大鼠肺动脉高压模型。MCT注射后连续给药4周。检测各组大鼠血流动力学指标,以原位末端标记法(TUNEL)染色检测右心室细胞凋亡情况,以蛋白质印迹法检测右心室B细胞淋巴瘤2(Bcl-2)、Bcl-2相关X蛋白(Bax)、活化的胱天蛋白酶-3(cleaved-caspase-3)、表皮生长因子受体(EGFR)、磷酸化EGFR(p-EGFR)、视神经萎缩症蛋白1(Opa1)和线粒体融合蛋白2(Mfn2)的蛋白表达情况。结果低、高剂量实验组和对照组、模型组右心室收缩压分别为(38.58±4.98)、(34.15±3.88)、(23.66±2.45)和(45.07±5.78)mmHg;平均肺动脉压分别为(27.85±3.77)、(24.25±3.09)、(17.33±2.46)和(33.07±4.15)mmHg;右心室/(左心室+室间隔)分别为(36.38±5.51)%、(33.63±4.69)%、(22.25±2.96)%和(42.50±7.33)%;右心室/胫骨长度分别为(69.33±7.86)、(62.69±7.17)、(49.12±6.42)和(78.22±9.07)mg·cm^(-1)。低、高剂量实验组的上述指标与模型组比较,在统计学上差异均有统计学意义(均P<0.01)。低、高剂量实验组Bcl-2、Bax、cleaved caspase-3、p-EGFR、Opa1、Mfn2与模型组相比,在统计学上差异均有统计学意义(P<0.05,P<0.01)。结论埃克替尼能够抑制MCT诱导的PH大鼠右心室重构,其机制可能与其降低右心室p-EGFR水平、缓解线粒体功能紊乱、抑制心肌细胞凋亡有关。
Objective To investigate the effect of icotinib on right ventricular remodeling in rats with monocrotaline(MCT)-induced pulmonary hypertension(PH).Methods Sprague-Dawley rats were randomly divided into control group(0.3% sodium carboxymethyl cellulose),model group and low,high dose experimental groups(30,60 mg·kg^(-1) icotinib),8 rats in each group.PH rat model was established by single intraperitoneal injection of 60 mg · kg^(-1) MCT in model group and low,high dose experimental groups.The drug was administered continuously for 4 weeks after MCT injection.The hemodynamic indexes of each group were detected.Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling(TUNEL)staining was used to detect the apoptosis of right ventricular cardiomyocytes.The protein levels of B cell lymphoma-2(Bcl-2),Bcl-2 associated X protein(Bax),cleaved cysteine aspartic acid specific protease-3(cleaved-caspase-3),epidermal growth factor receptor(EGFR),phosphorylated EGFR(p-EGFR),optic atrophy 1(Opal) and mi tofu sin 2(Mfn2) were detected by Western blot analysis.Results The right ventricular systolic pressure in low,high dose experimental groups and control group,model group were(38.58±4.98),(34.15±3.88),(23.66±2.45) and(45.07±5.78) mmHg;the mean pulmonary artery pressure were(27.85±3.77),(24.25±3.09),(17.33±2.46) and(33.07±4.15) mmHg;the right ventricle(RV) to left ventricle+septum were(36.38±5.51) %,(33.63±4.69) %,(22.25±2.96) % and(42.50±7.33) %;the RV to tibial length were(69.33±7.86),(62.69±7.17),(49.12±6.42) and(78.22±9.07) mg · cm^(-1).There were significant differences in the above indexes between low,high dose experimental groups and model group(all P <0.01).There were significant differences in Bcl-2,Bax,cleaved caspase-3,p-EGFR,Opa1,Mfn2 between low,high dose experimental groups and model group(P <0.05,P <0.01).Conclusion Icotinib can inhibit right ventricular remodeling in PH rats induced by MCT,and its mechanism may be related to reducing the phosphorylation level of EGFR in the right ventr
作者
胡霞
顾文强
严静静
黄维琳
李先伟
HU Xia;GU Wen-qiang;YAN Jing-jing;HUANG Wei-lin;LI Xian-wei(Department ofFundamental Education,Anhui College of Traditional Chinese Medicine,Wuhu 241000,Anhui Province,China;Departmentof Pharmacology,School of Pharmacy,Wannan Medical College,Wuhu 241002,Anhui Province,China)
出处
《中国临床药理学杂志》
CAS
CSCD
北大核心
2024年第12期1784-1788,共5页
The Chinese Journal of Clinical Pharmacology
基金
安徽省高校自然科学研究重大基金资助项目(KJ2021ZD0106)
安徽省高校自然科学研究重点基金资助项目(2023AH053200)。
关键词
埃克替尼
右心室重构
表皮生长因子受体
线粒体功能障碍
icotinib
right ventricular remodeling
epidermal growth factor receptor
mitochondrial dysfunction
