内源性血红素氧合酶-1/一氧化碳系统对动脉粥样硬化形成的抑制作用

目的 探讨动脉粥样硬化(AS)形成中血红素氧合酶-1(HO-1)/一氧化碳(CO)系统的变化、对AS进程的影响及其可能作用机制.方法 新西兰大白兔随机分为四组:对照组、胆固醇组、血红素组及卟啉锌组,每组8只.其中对照组喂饲普通饲料,胆固醇组喂饲含1.5%胆固醇饲料,血红素组及卟啉锌组在予以高胆固醇饮食的同时,分别经腹腔注射氯化血红素(HO激动剂,15 mg·kg~(-1)·d~(-1))或锌原卟啉-9(HO抑制剂,45 μmol·kg~(-1)·d~(-1)),共12周.检测各组①主动脉NOS、HO-1活性,NO、CO生成量,HO-1、ET-1的mRNA及蛋白表达;②血NO、ET-1水平.结果 ①与对照组比较, 高胆固醇饮食各组血清脂质、ox-LDL显著升高( P均<0.01 ), 但三组间差异均无统计学意义.②与对照组比较,胆固醇组主动脉cNOS活性及NO生成量明显降低,HO-1表达及CO生成量明显增高(P均<0.01),主动脉斑块面积为(54.00±4.16)%;锌原卟啉-9显著降低HO-1表达及CO生成量,主动脉壁粥样硬化损伤严重、斑块面积高达[(61.13±3.50)%].与胆固醇组比较,血红素干预显著增高HO-1表达及CO生成量,主动脉斑块面积[(17.88±3.01)%]显著减小(P均<0.01).③与胆固醇组比较,血红素干预显著降低ET-1 mRNA表达及含量,锌原卟啉-9显著增高ET-1 mRNA表达及含量(P均<0.01). 结论 HO-1/CO系统具有抗AS作用,该作用并非通过其对血脂和ox-LDL的调节实现,可能与该系统调节和代偿NOS/NO系统以及下调ET-1表达从而抑制血管平滑肌细胞增殖有关.

Inffluence of heme oxygenase-1-endogenous carbon monoxide system on atherosclerotic process

Objective To study the change and influence of heme oxygenase/carbon monoxide system in atherosclerosis and the possible role mechanism of the systems on atherosclerotic progress. Methods The rabbits received 1.5% cholesterol diet(Ch group,n=8) or 1.5% cholesterol diet plus HO-1 inducer hemin(Hm group,n=8) or HO-1 inhibitor zincprotoporphyrin IX(Znpp-IX, Zn group,n=8) by injection in abdominal cavity for 12 weeks. Results Compared with control group(C group, n=8), sercum levels of lipids and ox-LDL increased obviously in all experimental groups. However, they were not much different among three experimental groups.Compared with control group, aortic NO production and cNOS activity decreased markedly, CO production and HO-1 activity increased markedly (all P<0.01),the aortic plaques area was (54.00±4.16)% in Ch group; CO production and HO-1 activity decreased markedly in Zn group.Compared with Ch group, aortic HO activity and CO production eleveated markedly, the aortic lesion and plaques area [(17.88±3.01)%] reduced distinctly in Hm group;the aortic lesion and plaques area [(61.13±3.50)%] increased distinctly in Zn group. Compared with Ch group, aorta ET-1 expression of Hm group reduced markedly while in Zn group they were higher significantly than Ch group. Conclusion HO-1/CO system in atherosclerosis could play the inhibitory role against atherosclerotic lesion. The role is not carried out by the system which regulates sercum lipids and ox-LDL , but is related to the reciprocal relationship between HO-1/ CO and NOS/NO system in atherosclerosis and the system that intervene the expression of ET-1 and inhibits the proliferation of vascular smooth muscle cells.