血红素加氧酶-1抑制兔动脉粥样硬化进展与稳定斑块的作用  

Heme oxygenase-1 inhibits atherosclerosis progression and promotes plaque stability in a rabbit model

作　　者：李婷婷[1] 郭媛[1] 赵玉霞[2] 张建宁[3] 彭洁[1] 张运[1] 

机构地区：[1]教育部和卫生部心血管重构与功能研究重点实验室,山东大学齐鲁医院心内科,济南250012 [2]山东大学齐鲁医院中医科,济南250012 [3]山东大学齐鲁医院ICU,济南250012

出　　处：《山东大学学报（医学版）》2011年第6期64-70,共7页Journal of Shandong University:Health Sciences

基　　金：山东省科技攻关计划资助课题(2007GG20002025)

摘　　要：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 explore the role of heme oxygenase-1 （ HO71 ） in plaque progression and stabilization in atherosclerotic rabbits. Methods After abdominal aortic balloon injury, 45 male New Zealand White rabbits were fed with an atherogenic diet for 24 weeks. From week 12 to week 24, animals were randomly divided into three groups, respectively receiving intraperitoneal injection of heroin to induce HO-1 （hemin group）, Sn-protoporphyrin IX （SnPP） to inhibit HO-1 （SnPP group）, and vehicle as controls. Vulnerable plaques were established by local transfection with the p53 gene, and challenged with injection of Russell＇s viper venom and histamine to induce plaque rupture. Then all the rabbits were killed and their abdominal aortas were taken out to undergo oathological examination try and real-time RT-PCR were performed to determine expressions of matrix mctalloproteinase-9, interleakin-6 and tumor necrosis factor-or. Results Hemin induced an increase in HO-1 mRNA, protein and enzyme activity in atherosclerotic plaques. This induction was correlated with a reduction in the progression of plaque size and modulations in morphological features and plaque composition toward increased stabilization, ie, thicker fibrous cap, more intra-plaque smooth muscle cells and collagen content, and less macrophages and lipid content. Additionally, expressions of inflammatory mediators, including matrix metalloprotelnase-9, interleukin-6 and tumor necrosis factor-α were also lowered by heroin treatment （all P 〈0.01 ）. In contrast, SnPP treatment induced a reverse effect and augmented plaque progression and vulnerability. After pharmacological triggering, plaque rupture appeared in 5 rabbits in the control group（33% ）, 12 lnthe SnPPgroup （80%, P〈0.05） and none in the hemin group （0%, P〈0.05）. Conclusion HO-1 inhibits progression of advanced atherosclerotic plaques and promotes plaque stability, probably by modulating plaque composition and attenuating plaque inflammation.

关 键 词：动脉粥样硬化 易损斑块 炎症 血红素加氧酶 

分 类 号：R541.4[医药卫生—心血管疾病]