PDF(Pubmed)
Abstract：
Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE-/- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG (p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG (p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG (p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE-/- mice delayed the atherosclerosis progression and enhanced plaques\' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.
摘要：
波生坦,内皮素受体拮抗剂（ERA），具有潜在的抗动脉粥样硬化特性。我们研究了波生坦和阿托伐他汀对糖尿病小鼠动脉粥样硬化病变的进展和组成的补充作用。48只雄性ApoE-/-小鼠饲喂高脂肪饮食(HFD)14周。在第8周，用链脲佐菌素诱导糖尿病，将小鼠随机分为四组:(1)对照/COG:无干预;(2)ΒOG:波生坦100mg/kg/天/口;(3)ATG:阿托伐他汀20mg/kg/天/口;和(4)BO+ATG:波生坦和阿托伐他汀的联合给药。胶原的斑块内含量，弹性蛋白,单核细胞趋化蛋白-1（MCP-1），肿瘤坏死因子-a(TNF-a),基质金属蛋白酶（MMP-2，-3，-9），和TIMP-1测定。所有治疗组的管腔狭窄百分比均显着降低：BOG：19.5±2.2％，ATG:12.8±4.8%,和BO+ATG：与对照组相比，9.1±2.7％（24.6±4.8％，p<0.001)。与COG相比,阿托伐他汀和波生坦的施用导致显著更高的胶原含量和更厚的纤维帽(p<0.01)。与COG相比，所有干预组的MCP-1，MMP-3和MMP-9的相对斑块内浓度较低，TIMP-1浓度较高（p<0.001）。重要的是,与COG相比,波生坦联合阿托伐他汀后的参数水平较低(p<0.05).波生坦治疗糖尿病，动脉粥样硬化ApoE-/-小鼠延缓了动脉粥样硬化的进展并增强了斑块的稳定性，显示适度的，但与阿托伐他汀的累加效应，在动脉粥样硬化性心血管疾病中很有前途。
