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目的探讨血红素加氧酶-1(HO-1)对兔动脉粥样硬化进展及斑块稳定性的作用。方法采用高脂饲料加腹主动脉内膜剥脱术建立兔动脉粥样硬化模型后,45只成模雄性新西兰兔随机分为3组,每组15只,继续给予高脂饲料(对照组),同时经腹腔注射HO-1诱导剂氯化血红素(血红素组)或HO-1抑制剂锌锡原卟啉-9(卟啉锡组)。干预12周后,在腹主动脉斑块处转染携带人野生型p53基因,2周后给予鲁塞尔蝰蛇毒和组胺触发,造成实验性斑块破裂、血栓形成。取腹主动脉观测斑块的病理形态及组成,通过免疫组织化学及实时定量RT-PCR分析,测定斑块内炎性因子基质金属蛋白酶-9、肿瘤坏死因子-a和白介素-6的表达。结果 与对照组相比,血红素组斑块内HO-1的表达及活性显著增加,腹主动脉内-中膜厚度显著减小,纤维帽厚度增加,平滑肌细胞和胶原含量增多,而巨噬细胞和脂质浸润减少,炎症因子的表达水平降低(P均<0.01)。相反,使用锡原卟啉-9抑制HO-1的产生及活性,促进了斑块的进展,增加了斑块内炎症因子的水平与斑块的易损性(P均<0.01)。药物触发后,卟啉锡组斑块破裂率显著高于对照组(80%vs 33%,P<0.05),而血红素组兔斑块均未发生破裂(0%vs 33%,P<0.05)。结论 HO-1可抑制动脉粥样硬化进展,增加斑块的稳定性,其机制可能与调节斑块结构和成分,抑制斑块内炎症有关。
Objective To investigate the effect of heme oxygenase-1 (HO-1) on the development of atherosclerosis and plaque stability in rabbits. Methods Forty-five male New Zealand white rabbits were randomly divided into three groups (15 rats in each group). The animals in the control group were given high-fat diet (control group) At the same time, HO-1 inducing agent hemin (heme group) or HO-1 zinc tin protoporphyrin-9 (porphyrin tin group) were injected intraperitoneally. Twelve weeks after the intervention, human wild-type p53 gene was transfected in abdominal aortic plaque and two weeks later, ruther viper venom and histamine were triggered, resulting in experimental plaque rupture and thrombosis. The pathological morphology and composition of the plaques were observed by abdominal aorta. The expression of MMP-9, TNF-a and IL-6 in the plaque was determined by immunohistochemistry and real-time RT-PCR analysis. Results Compared with the control group, the expression and activity of HO-1 in the heme group increased significantly, the intima-media thickness of the abdominal aorta decreased significantly, the thickness of the fibrous cap increased, the content of smooth muscle cells and collagen increased, Cells and lipid infiltration decreased, the expression of inflammatory cytokines decreased (all P <0.01). In contrast, the use of protoporphyrin-9 to inhibit the production and activity of HO-1 promoted plaque progression and increased plaque inflammatory cytokines and plaque vulnerability (all P <0.01). After the drug was triggered, the rupture rate of plaque in the porphyrin-tin group was significantly higher than that in the control group (80% vs 33%, P <0.05), but no rupture in the heme group (0% vs 33%, P <0.05 ). Conclusion HO-1 can inhibit the progression of atherosclerosis and increase the stability of plaque. The mechanism may be related to regulating the structure and composition of plaque and inhibiting the plaque inflammation.