中文摘要：

目的利用多西环素的非特异性基质金属蛋白酶抑制剂特性,研究该药对高血压性主动脉重塑的影响。方法80只7周龄雄性卒中易感型自发性高血压（SHR-SP）大鼠随机分为药物干预组和对照组,同时饲养同周龄雄性WKY大鼠。药物干预组每天经自由饮水给予多西环素30mg/（kg.d）。观察6个月后处死动物留取主动脉,一部分组织用于制备石蜡切片并进行HE、维多利亚蓝（弹力纤维特异性染色）和vonKossa银（异常钙沉积染色）染色,另一部分组织用于交联胶原测定和明胶酶谱分析。结果两组高血压大鼠的主动脉内膜周长、外膜周长和血管中膜面积差异无显著性。采用明胶酶谱法,在各组均未检测到基质金属蛋白酶9活性;与对照组比较,药物干预组基质金属蛋白酶2活性显著降低（2.43±0.14比3.15±0.23,P〈0.05）。维多利亚蓝动脉弹力纤维染色分析显示,与对照组比较,药物干预组弹力纤维占中膜面积百分比显著降低[3.46%±1.62%比5.72%±3.87%,P〈0.05]。药物干预组交联胶原浓度与对照组比差异无统计学意义（26.4±7.0mg/g比28.0±8.7mg/g,P〉0.05）。与对照组比较,药物干预组钙沉积占中膜面积百分比虽无统计学差异,但存在降低的趋势[0.688%±0.718%比0.960%±0.999%,P=0.177]。结论多西环素可以抑制SHR-SP主动脉中基质金属蛋白酶2活性,但在血压没有得到有效控制的前提下会加重高血压性主动脉硬化的程度。

英文摘要：

Aim To investigate the effect of non-specific matrix metalloproteinases（MMP）inhibitor,doxycycline（DOX）,on hypertensive aortic remodeling.Methods 80 male stroke-prone spontaneously hypertensive rats（SHR-SP）of 7 weeks age were randomly divided into 2 groups（DOX and control group,respectively,n=40 each）.Five male Wistar-Kyoto rats（WKY）with same age were also investigated.SHR-SP were chronically treated from the end of 7 weeks after birth with doxycycline（30 mg/（kg·d））in drinking water.Follow-up was terminated when the mortality rate of control group reached 50%.Rats were killed,and aorta was dissected and prepared for histological and biochemical assays.For pathological analysis,we used hematoxylin and eosin（HE）staining,Victoria blue（elastic fiber staining）and von Kossa silver（calcium staining）.For biochemical analysis,soluble collagen assay and gelatin zymography were carried out.Results There were no difference in intima perimeter,adventitia perimeter and media area in hypertensive rats.MMP-9 activity by gelatin zymography was not detected in all animals.Compared with control group,MMP-2 activity in dox group were significantly reduced（2.43±0.14 vs 3.15±0.23,P0.05）.Compared with control group,the ratio of elastic fiber area to intima area was dramatically decreased in DOX group [（3.46%±1.62% vs 5.72%±3.87%,P0.05）].Sircol soluble collagen assay showed that there had no statistical difference between control and DOX groups（26.4±7.0 mg/g vs 28.0±8.7 mg/g,P0.05）.Although calcium deposition as revealed by von Kossa silver staining was no statistical difference between control and DOX groups,there was decreasing trend in DOX group（0.688%±0.718% vs 0.960%±0.999%,P=0.177）.Conclusion Despite the fact that doxycycline could inhibit aortic MMP-2 activity in SHR-SP,in the setting of uncontrolled hypertension,doxycycline may aggravate the process of hypertensive aortic stiffening.