非诺多泮抑制小鼠胸主动脉瘤的实验研究

The repressing effect of fenoldopam on the development of thoracic aortic aneurysm in mice

目的探讨多巴胺一型受体激动剂非诺多泮(FNDP)是否对小鼠胸主动脉瘤(TAA)具有保护作用。方法对3周龄的雄性C57BL/6J小鼠采用β-氨基丙腈(BAPN)复制TAA模型。25只小鼠分为三组:对照组、BAPN组、BAPN+FNDP组(腹腔注射FNDP)。统计TAA的发生率和生存率,观察胸主动脉的大体变化,弹力蛋白(Elastin)染色观察形态学改变。免疫组化法检测基质金属酶2(MMP2)、基质金属酶9(MMP9)和白细胞分化抗原68(CD68)的变化。明胶酶谱法检测MMP2和MMP9的活性。反转录聚合酶链式反应(RT-PCR)法检测多巴胺受体1(D1DR)、多巴胺受体2(D2DR)、多巴胺受体3(D3DR)、多巴胺受体5(D5DR)、白介素-1β(IL-1β)、白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、单核细胞趋化蛋白-1(MCP-1)、α-平滑肌肌动蛋白(α-SMA)及平滑肌蛋白22α(SM22α)的mRNA表达情况。结果与对照组相比,BAPN组有明显的TAA形成,胸主动脉壁弹力纤维紊乱与断裂,且D1DR和D5DR的mRNA水平均显著下降。与BAPN组相比,BAPN+FNDP组小鼠TAA的形成率和动脉瘤破裂率明显降低;胸主动脉壁的弹力纤维紊乱与断裂明显改善;胸主动脉壁内MMP2和MMP9的表达水平均显著下降,血清中MMP2的酶活性显著降低;胸主动脉壁中巨噬细胞浸润显著降低,且IL-1β、IL-6、TNF-α和MCP-1的mRNA水平均显著下降;α-SMA和SM22αmRNA表达水平无显著差异。结论FNDP可抑制小鼠TAA的进展,有可能成为治疗TAA的一个潜在药物。

Objective To investigate whether fenoldopam(FNDP)(an agonist of type 1 dopamine receptor)has a protective effect on thoracic aortic aneurysm(TAA)in mice.Methods Three-week-old male C57BL/6J mice were treated withβ-aminopropionitrile(BAPN)to induce TAA.The mice were divided into three groups:the control group,the BAPN group,and the BAPN+FNDP group(FNDP injected intraperitoneally).The incidence and survival rate of TAA were recorded.Gross anatomy of the whole aortae was observed.Elastin staining was performed to assess morphological change,while immunohistochemistry was employed to evaluate the expressions of matrix metalloproteinase 2(MMP2),matrix metalloproteinase 9(MMP9)and cluster of differentiation 68(CD68)respectively.Gelatin zymography was conducted to assess MMP2 and MMP9 activity.Reverse transcription-polymerase chain reaction(RT-PCR)was performed to measure the mRNA expression levels of dopamine receptor D1(D1DR),dopamine receptor d2(D2DR),dopamine receptor d3(D3DR),dopamine receptor d5(D5DR),interleukin-1β(IL-1β),interleukin-6(IL-6),tumour necrosis factor-α(TNF-α),monocyte chemoattractant protein-1(MCP-1),alpha-smooth muscle actin(α-SMA)and smooth muscle protein 22-alpha(SM22α).Results Compared to the control group,the BAPN group exhibited significant formation of TAA.Elastic fiber disruption was also observed in the thoracic aortic wall,along with a significant decrease in the mRNA levels of D1DR and D5DR.The BAPN+FNDP group showed a significant reduction in the incidence of TAA formation and the rate of aneurysm rupture compared to the BAPN group.The disruption and rupture of elastic fibers in the thoracic aortic wall were significantly improved in the BAPN+FNDP group.The levels of MMP2 and MMP9 in the thoracic aortic wall significantly decreased,and the enzymatic activity of MMP2 in the serum was significantly reduced.Moreover,macrophage infiltration in the thoracic aortic wall was significantly reduced and the mRNA levels of IL-1β,IL-6,TNF-αand MCP-1 also significantly decreased after FNDP treatment.There was no statistically significant difference in the mRNA levels ofα-SMA and SM22α.Conclusion FNDP shows an inhibitory effect on TAA progression in mice,suggesting a potential of FNDP as a therapeutic agent for TAA.