吡非尼酮改善自发性高血压大鼠心肌及主动脉纤维化

Pirfenidone improves myocardial and aortic fibrosis in spontaneously hypertensive rats

目的探讨吡非尼酮能否改善高血压导致的心脏及主动脉纤维化。方法Wistar-Kyoto大鼠(WKY)10只,自发性高血压大鼠(SHR)12只。适应性喂养后利用简单随机方法分为4组:WKY+溶剂组(n=5),WKY+吡非尼酮组(n=5),SHR+溶剂组(n=6),SHR+吡非尼酮组(n=6)。分别予以生理盐水或吡非尼酮(200 mg·kg^(-1)·d^(-1))灌胃,持续8周。连续监测大鼠尾动脉血压。8周后,心脏超声测定大鼠心脏结构和功能变化,病理实验检测大鼠心脏及主动脉形态变化,分子生物实验测定纤维蛋白原和波形蛋白等纤维化标志物水平。结果SHR尾动脉压明显高于WKY(均为P<0.01),吡非尼酮干预与生理盐水干预相比,大鼠血压无统计学差异。与WKY+溶剂组相比,SHR+溶剂组心肌血管周围和间质胶原含量分别增加了131.3%和126.9%,纤维蛋白原和波形蛋白表达含量分别增加了112.0%和241.0%(均为P<0.01)。与SHR+溶剂组相比,SHR+吡非尼酮组心肌血管周围和间质胶原含量分别下降了41.1%和44.9%,纤维蛋白原和波形蛋白表达含量分别下降了43.3%和42.2%(均为P<0.01)。胸主动脉染色显示,与SHR+溶剂组相比,SHR+吡非尼酮组胶原含量减少了29.3%,SHR+吡非尼酮组纤维蛋白原含量下降了26.5%(均为P<0.01)。弹力纤维染色显示,SHR+溶剂组较WKY+溶剂组弹力纤维含量减少了37.9%,SHR+吡非尼酮组较SHR+溶剂组弹力纤维含量增加了61.0%(P<0.01)。结论吡非尼酮不影响大鼠血压,但可缓解SHR心肌和主动脉纤维化,减轻心肌和主动脉重构,改善主动脉弹性。

Objective To investigate whether pirfenidone can improve cardiac and aortic fibrosis caused by hypertension.Methods After adapting feeding,10 Wistar-Kyoto rats(WKY)and 12 spontaneously hypertensive rats(SHR)were divided into 4 groups using a simple random method:WKY+solvent group(n=5),WKY+pirfenidone group(n=5),SHR+solvent group(n=6),SHR+pirfenidone group(n=6).The rats were accepted pirfenidone(200 mg·kg^(-1)·d^(-1))or solvent with equivalent volume by daily intragastric administration for 8 weeks.The blood pressure of the tail artery was weekly monitored.After 8 weeks,the structural and functional changes of rat heart was measured by echocardiography,the morphological changes of rat heart and aorta was detected by pathological test,and the level of fibrosis markers such as fibronectin and vimentin was measured by molecular biological test.Results The tail arterial pressure of SHR was significantly higher than that of WKY(all P<0.01),but there was no significant difference between pirfenidone and solvent group.Compared with WKY+solvent group,the expression of myocardial perivascular and interstitial collagen in SHR+solvent group increased by 131.3%and 126.9%,and the expression of fibronectin and vimentin increased by 112.0%and 241.0%(all P<0.01),respectively.Compared with SHR+solvent group,the myocardial collagen in SHR+pirfenidone group decreased by 41.1%and 44.9%,fibronectin and vimentin decreased by 43.3%and 42.2%(all P<0.01),respectively.Compared with SHR+solvent group,the collagen content in SHR+pirfenidone group decreased by 29.3%,and fibronectin content decreased by 26.5%(both P<0.01).EVG staining showed the elastic fibers in SHR+solvent group decreased by 37.9%compared with WKY+solvent group,and the elastic fibers in SHR+pirfenidone group increased by 61.0%compared with SHR+solvent group(P<0.01).Conclusions Pirfenidone does not affect blood pressure in rats,but can alleviate SHR myocardial and aortic fibrosis,reduce myocardial and aortic remodeling,and improve aortic elasticity.