氯沙坦减轻自发性高血压大鼠视网膜毛细血管细胞凋亡

Losartan Alleviate the Apoptosis in Retinal Capillary in Spontaneously Hypertensive Rats

背景原发性高血压(EH)易造成视网膜血管损伤,伴随有血管内皮细胞凋亡。有研究表明血管紧张素Ⅱ(AngⅡ)能够通过其受体诱导血管内皮细胞发生凋亡,氯沙坦减少高血压靶器官对AngⅡ的反应,降低外周阻力、改善血管重构,对心血管系统起到有利的作用,但氯沙坦是否能逆转高血压视网膜病变中微血管的形态和功能,是否减少视网膜微血管凋亡现在仍不清楚。目的观察自发性高血压大鼠(SHR)视网膜毛细血管形态,研究氯沙坦对SHR视网膜毛细血管细胞凋亡的作用。方法将12周龄雄性SHR随机分成SHR氯沙坦组[氯沙坦30 mg/(kg.d),灌胃,n=10]与对照组(对照组,n=10),另设12周龄雄性Wistar-Kyoto大鼠作正常对照组(WKY,n=10)。实验前及实验开始后测大鼠鼠尾动脉收缩压1次/4周。饲养8周后,采用透射电镜、视网膜消化铺片的HE染色、原位DNA末端酶标记技术(TUNEL)和免疫组化法检测视网膜毛细血管细胞凋亡情况。结果氯沙坦能显著降低SHR的收缩压,显著降低视网膜毛细血管细胞凋亡率[SHR组(28.9±7.2)%比氯沙坦组(7.3±5.5)%比WKY组(2.4±1.9)%,P<0.01],但仍未达到WKY组的水平(P<0.05)。电镜下对照组毛细血管周细胞有早期凋亡表现,内皮细胞核轻度异常,氯沙坦组未见异常。氯沙坦减轻SHR bax的表达(P<0.01),增加bcl-2但未能达到WKY大鼠水平(P>0.05)。结论氯沙坦不仅有明显的降压作用,而且在高血压病程中可抑制视网膜毛细血管内皮细胞和周细胞凋亡。

Background and Objective Sustained hypertension induces retinal blood vessels injury associated with endothelial cells disfunction and apoptosis. Angiotensin Ⅱ receptor has been reported to induce apoptosis of endothelial cells. However, there is scant data regarding whether losartan improves the microcirculation such as retinal vascular morphology and function in retinopathy and the effect on retinal microvascular apoptosis is not unknown. This study was aimed to determine the effects of losartan on apoptosis in retinal capillary in spontaneously hypertensive rats [SHR）. Methods Sex and age matched SHR were randomized to receive following approaches： losartan treatment （30 mg/kg ·d by gavage, n= 10） or placebo （n= 10）, Wistar-Kyoto rats （WKY） （n= 10） as control groups. Systolic blood pressures were measured by a tail-cuff method before and every four weeks during experiment. Retina was study histologically by using hematoxylin and eosin （HE） staining and transmission electronic microscope. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling （TUNEL） methods were used for assessment of cell apoptosis Bax and bcl-2 by immunochemistry. Results A large area of cell-free capillary was occurred in SHR. The chromatin of nuclei labeled bythe TUNEL method was distributed unequally, displaying apoptosis characteristics. Losartan significantly decreased SBP in SHR（P〈0.01）. Losartan significantly decreased the apoptosis index in retina（SHR： 28. 9%±7.2% vs SHR-Los： 7.3%±5.5% vs WKY： 2.4%± 1.9 %, P〈0.01）. Transmission electron microscopy showed early sign of apoptosis in SHR, while losartan alleviate the abnormal alteration. Conclusion Our data showed losartan prevent the cell apoptosis of retinal capillary in the development of hypertensive retinopathy.