ANALYSES OF ANTI-ATHEROGENIC PROPERTIES OF HEME OXYGENASE-1

我们对动脉粥样硬化过程和引发缺血性心血管疾病的因素的理解的最新进展导致了对抗氧化反应或外源性抗氧化剂的考虑，这些抗氧化剂被认为可以抑制动脉壁的多种致动脉粥样硬化和血栓形成前事件。血红素加氧酶（HO）是血红素降解所必需的酶，已被证明具有这种抗氧化特性，通过产生胆汁色素，一氧化碳和铁蛋白诱导。我们已经证明，在人主动脉内皮细胞和平滑肌细胞共培养中，轻度氧化的LDL显著诱导HO-1（一种可诱导形式的HO），其诱导导致轻度氧化LDL诱导的单核细胞趋化性减弱。我们也证实了HO-1在人、鼠和兔的动脉粥样硬化组织中大量表达。通过调节ldl受体敲除小鼠和Watanabe遗传性高脂血症兔在其动脉粥样硬化病变发展过程中的HO活性，通过对动脉粥样硬化病变形成的定量分析，证明了HO的抗动脉粥样硬化特性。HO表达与血浆和组织脂质过氧化物水平呈负相关。HO对一氧化氮通路也有影响。这些观察结果可能表明，在动脉粥样硬化过程中诱导的HO是血管壁的内在保护途径。

Recent developments in our understanding of the atherosclerotic process and factors that trigger ischemic cardiovascular disease have led to the consideration of antioxidative responses or exogenous antioxidants, which are proposed to inhibit multiple proatherogenic and prothrombotic events in arterial wall. Heme oxygenases (HO), an enzyme essential for heme degradation, have been shown to have such antioxidative properties via the production of bile pigments, carbon monoxide and ferritin induction. We have demonstrated that mildly oxidized LDL markedly induces HO-1, an inducible form of HO, in human aortic endothelial and smooth muscle cell cocultures and that its induction results in the attenuation of monocytes chemotaxis induced by mildly oxidized LDL. We also confirmed abundant expression of HO-1 in human, murine and rabbit atheroscleroticlesions. By modulating HO activities in LDL-receptor knockout mice and Watanabe heritable hyperlipidemic rabbits during their atherosclerotic lesion developments, anti-atherogenic properties of HO have demonstrated as judged by the quantitative analyses of atherosclerotic lesion formation. HO expression was inversely correlated with the levels of plasma and tissue lipid peroxides. HO also influenced on nitric oxide pathway. These observations may suggest that HO, induced during atherosclerotic process, functions as an intrinsic protective pathway in vascular wall.