Prevention of atherosclerotic plaque rupture by the regulation of oxygen radical metabolism of vascular wall cells.

最近的研究表明，心肌梗死并不是高度进展的动脉粥样硬化病变，而是相对轻微的病变。因此，预防不稳定冠脉斑块破裂是预防急性心肌梗死的必要手段。在这项研究中，我们研究了血管平滑肌细胞中氧自由基的调节是否可以调节动脉粥样硬化斑块的稳定性。第一年，我们证明了热休克或肿瘤坏死因子-α的预适应可诱导培养的血管平滑肌细胞产生抗氧化酶，并获得对氧化应激的耐受性。在第二年，我们发现加入反义寡核苷酸抑制了肿瘤坏死因子-α诱导的超氧化物歧化酶的产生，同时也消除了对氧化应激的耐受性。另一方面，将锰-超氧化物歧化酶脂质体介导入细胞线粒体，增强了细胞对氧化应激的耐受性。这些结果提示，血管壁细胞抗氧化酶的表达与血管平滑肌细胞的存活密切相关，通过在细胞内引入抗氧化酶可以稳定动脉粥样硬化斑块。

Recent studies revealed that myocardial infarction is not occurred from highly progressive atherosclerotic lesions, but rather from relatively mild lesions. Therefore, prevention of rupture of unstable coronary plaque is necessary for the prevention of acute myocardial infarction. In this study, we examined whether regulation of oxygen radical in vascular smooth muscle cells can modulate stability of atherosclerotic plaque. In the first year, we demonstrated that antioxidative enzyme, Mn-SOS, was induced in cultured vascular smooth muscle cells by the preconditioning with heat shock or TNF-α together with the acquisition of tolerance to oxidative stress. In the second year, we revealed that the induction of Mn-SOD by TNF-α was inhibited by the addition of antisenseoligodeoxyribonucleotide (AODN) to Mn-SOD and that the tolerance to oxidative stress was also abolished by the treatment with AODN. On the other hand, lipofection of Mn-SOD to smooth muscle cells introduced Mn-SOD in mitochondria of cells and augmented tolerance to oxidative stress. These results suggest that the expression of antioxidative enzyme in vascular wall cells is closely related to the survival of smooth muscle cells and that by introducing antioxidative enzyme in cells could stabilize atherosclerotic plaque.