阿托伐他汀对心肌纤维化影响的实验研究及其作用机制

Experimental study on the effects of atorvastatin in myocardial fibrosis and its effective machanisms

目的研究心肌纤维化时NAD(P)H氧化酶与转化生长因子(TGF)-β1、结缔组织生长因子(CTGF)的关系以及阿托伐他汀对心肌纤维化的作用。方法用两肾两夹法建立肾性高血压模型。给予阿托伐他汀10,5 mg·kg-1·d-1和坎地沙坦10 mg·kg-1·d-1,连续4周后,检测血流动力学参数、左心室/体重比率(LVW/BW);Masson染色检测心肌纤维化程度;Western-blot检测Nox4、TGF-β1和CTGF的表达。结果阿托伐他汀显著改善了高血压大鼠的心功能障碍和心肌纤维化程度,并且显著下调了Nox4、TGF-β1和CTGF在心肌组织的表达。结论阿托伐他汀能降低高血压大鼠心肌纤维化程度及改善心功能,其机制与抑制TGF-β1/Nox4/CTGF通路有关。

Objective To investigate the effect of the atorvastatin in the myocardial fibrosis and study the relationship of Nox 4 and connective tis-sue growth factor （ CTGF ） .Methods The two -kidney two -clip （2K2C） method was used to induce renovascular hypertension.After ator-vastatin （10, 5 mg· kg-1 · d-1 ） and candesartan （10 mg· kg -1 · d-1 ） were given for 4 weeks, hemodynamic parameters were measured and left ventricular weight to body weight （ LVW/BW） ratio was calculated.Mor-phological analysis was performed by using Masson staining.Western -blot was used to investigate the expression of Nox 4 , transforming growth factor（TGF） -β1 and CTGF in left ventricle （ LV）.Results Aortic systolic pressure （ AoSP） ,aortic diastolic pressure （ AoDP） ,left ventricu-lar end-systolic pressure （LVESP）,left ventricular end-diastolic pres-sure （ LVEDP） and LVW/BW ratio were markedly elevated while maxi-mum ascending rate of left ventricular pressure （＋dp/dtmax ） and maxi-mum declining rate of left ventricular （ -dp/dtmax ） were significantly decreased in 2K2C rats.Atorvastatin or candesartan could prevente the decrease in ＋dp/dtmax or -dp/dtmax, however, atorvastatin had no significant blood -lowing effects.LVW/BW ratio and left ventricular perivascular collagen fraction （ PCVF ） increased significantly in hyper-tension rats.Both atorvastatin and candesartan partly reversed these effects and improved the cardiac hypertrophy and fibrosis.The expressionof Nox4, TGF-β1 and CTGF increased significantly in LV of 2K2C rats while their levels were down -regulated with drugs given.Conclusion The Nox4 involves in myocardial fibrosis regulated by TGF -β1 and CTGF in renovascular hypertensive rats.Atorvastatin may attenuate myocardial fibrosis of 2K2C rats and improve their cardiac function , the inhibition of TGF-β1/Nox4/CTGF pathway possibly contributes to these effects.