西洛他唑抑制大鼠实验性腹主动脉瘤。
Suppression of experimental abdominal aortic aneurysm in a rat model by the phosphodiesterase 3 inhibitor cilostazol.
机构信息
Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.
出版信息
J Surg Res. 2011 May 15;167(2):e385-93. doi: 10.1016/j.jss.2011.01.017. Epub 2011 Feb 24.
BACKGROUND
The present experiments sought to determine whether cilostazol, a selective inhibitor of cyclic adenosine monophosphate (cAMP) phosphodiesterase 3 (PDE3), suppressed elastase-induced abdominal aortic aneurysm (AAA) development in a rat model.
METHODS
Male Sprague-Dawley rats (n = 16/each group) were randomly distributed into three groups: sham-, saline-, and cilostazol-. Rats of saline and cilostazol groups underwent intra-aortic elastase perfusion to induce AAAs, while rats of sham-group were perfused with saline. Rats of cilostazol-group received cilostazol treatment (100 mgkg(-1)d(-1)) for the entire experimental period. The areas of the lumen of the aortas at the segment with maximum diameter were measured preperfusion and on d 7, 14 after perfusion. Systolic blood pressure was measured by tail-cuff technique. Aortic tissue samples were harvested on d 14 after intra-aortic perfusion and evaluated by reverse transcription-polymerase chain reaction and Western blot for matrix metalloproteinase-2, 9 (MMP-2, 9), by immunohistochemistry for nuclear factor kappa B (NF-κB), and by Gomori aldehyde fuchsin for elastin. Activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and level of reactive oxygen species (ROS) in these samples were also measured.
RESULTS
On d 14, rats of saline-group had significantly increased aortic sizes compared with sham-group (P < 0.01), while, cilostazol treatment significantly reduced this increase (cilostazol- versus saline-, P < 0.01) without affecting blood pressure (P > 0.05). The expression of both MMP-2 and MMP-9 and the destruction of elastic fibers in aortic tissues were significantly decreased by cilostazol treatment (P < 0.05), probably through the suppression of NF-κB activation (P < 0.01). Consistently, cilostazol significantly inhibited NADPH oxidase activity (P < 0.01), accompanied by a reduced level of ROS (P < 0.01).
CONCLUSION
Cilostazol retards experimental AAAs development independently of blood pressure reduction possibly by inhibiting proteolysis, inflammation, and oxidative stress. Selective PDE3 inhibition may offer an additional method to pharmacologically inhibit AAAs.
背景
本实验旨在研究环磷酸腺苷单磷酸（cAMP）磷酸二酯酶 3（PDE3）选择性抑制剂西洛他唑是否能抑制弹性蛋白酶诱导的大鼠腹主动脉瘤（AAA）的发展。
方法
雄性 Sprague-Dawley 大鼠（每组 16 只）随机分为三组：假手术组、盐水组和西洛他唑组。盐水组和西洛他唑组大鼠经主动脉内弹性酶灌注诱导 AAA，假手术组大鼠用生理盐水灌注。西洛他唑组大鼠在整个实验期间接受西洛他唑治疗（100mg/kg/d）。在灌注前和灌注后第 7、14 天测量主动脉最大直径段的管腔面积。采用尾套法测量收缩压。在主动脉内灌注后第 14 天采集主动脉组织标本，采用逆转录聚合酶链反应和 Western blot 检测基质金属蛋白酶-2、9（MMP-2、9），免疫组织化学检测核因子 kappa B（NF-κB），Gomori 醛固酮复红检测弹力纤维。还测量了这些样本中烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶的活性和活性氧（ROS）的水平。
结果
在第 14 天，盐水组大鼠的主动脉直径明显大于假手术组（P<0.01），而西洛他唑治疗显著减少了这种增加（西洛他唑组与盐水组相比，P<0.01），但不影响血压（P>0.05）。MMP-2 和 MMP-9 的表达以及主动脉组织中弹性纤维的破坏均被西洛他唑治疗显著减少（P<0.05），可能是通过抑制 NF-κB 激活（P<0.01）。一致地，西洛他唑显著抑制 NADPH 氧化酶活性（P<0.01），同时降低 ROS 水平（P<0.01）。
结论
西洛他唑通过抑制蛋白水解、炎症和氧化应激来延缓实验性 AAA 的发展，独立于血压降低。选择性 PDE3 抑制可能为抑制 AAA 提供一种额外的药物治疗方法。
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