替米沙坦通过调节Krüppel样因子4的表达延缓心肌纤维化

Telmisartan reverses myocardial fibrosis by regulating the expression of Krüppel-like factor 4

目的研究SHR大鼠心肌Krüppel样因子4(KLF4)及其相关因子变化,同时观察替米沙坦治疗后的效果。方法 10周左右的SHR大鼠分别给予生理盐水和替米沙坦10 mg·kg-1·d-1干预(WKY为对照组)。8周后测血压,左室重量及左室重量指数评定左室肥厚情况;同时观察心肌组织中KLF4、内皮一氧化氮合酶(e NOS)及纤溶酶原激活抑制物-1(PAI-1)、基质金属蛋白酶抑制物-1(TIMP-1)和Ⅳ型胶原的mRNA和蛋白表达水平的变化。为进一步明确其机制,用AngⅡ刺激内皮细胞,同时测定KLF4的表达进一步明确病理机制。结果 SHR大鼠血压、左室重量(LVW)及左室重量指数(LVW/BW)较WKY大鼠明显增加(均为P<0.05),替米沙坦可以显著降低血压,逆转SHR大鼠的LVW及LVW/BW变化(均为P<0.01)。SHR大鼠KLF4、e NOS的mRNA及蛋白表达水平较WKY大鼠显著降低(均为P<0.05),而替米沙坦治疗组KLF4的表达较SHR组明显增加(均为P<0.05);相反,SHR大鼠PAI-1、TIMP-1和Ⅳ型胶原的mRNA及蛋白水平较WKY大鼠明显增加(均为P<0.05),而替米沙坦治疗后较SHR组明显降低(均为P<0.05)。AngⅡ作用于内皮细胞,e NOS的磷酸化明显降低(2.37±0.22比1.57±0.31)(P<0.05),同时PAI-1、TIMP-1和Ⅳ型胶原的表达明显增加(均为P<0.05),过表达KLF4可以使e NOS的磷酸化显著回升(1.57±0.31比2.08±0.28)(P<0.05),同时PAI-1、TIMP-1和Ⅳ型胶原的表达较AngⅡ作用下明显减低(均为P<0.05)。结论KLF4在高血压大鼠心肌心肌纤维化过程中发挥重要作用,替米沙坦降压治疗可以明显延缓或逆转此病理过程。

Objective To explore the change and the effect of telmisartan on Krüppel-like factor 4and its related factors in SHR rats myocardial fibrosis. Methods Ten-week-old male SHR rats were fed standard chow diet and treated with telmisartan( 10 mg·kg- 1·day- 1) for 8 weeks,while WKY rats are used as control,fed standard chow diet and treated with normal saline. Systolic arterial pressure was measured by tail-cuff plethysmography. The left ventricular weight and left ventricular mass index were used to evaluate the ventricular hypertrophy. At the same time,we observed the changes of mRNA and protein of KLF4,endothelial nitric oxide synthase( e NOS), plasminogen activator inhibitor-1( PAI-1), matrix metalloproteinase inhibitor-1( TIMP-1) and collagen type Ⅳ in the myocardial tissue. Results The blood pressure,left ventricular mass( LVW) and left ventricular mass index( LVW / BW) of SHR rats increased significantly comparing with WKY rats,telmisartan can significantly reduce blood pressure,LVW and LVW / BW. The mRNA and protein levels of KLF4 and e NOS of SHR rats decreased significantly than that in WKY rats,while telmisartan increased their level. The mRNA and protein level of PAI-1,TIMP-1 and Collagen type Ⅳ of SHR rats increased significantly than that in WKY rats,whereas telmisartan eliminated these effect. Overexpression KLF4 in endothelial cell can reverse the effect of AngⅡ. Conclusions KLF4 plays an important role in the process of myocardial fibrosis,telmisartan treatment can significantly slow or reverse the pathological process through KLF4.