Interferon regulatory factors regulate interleukin-1β-converting enzyme expression and apoptosis in vascular smooth muscle cells
Interferon regulatory factors regulate interleukin-1β-converting enzyme expression and apoptosis in vascular smooth muscle cells
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DOI：
10.1161/01.hyp.33.1.162
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发表时间：
1999-01-01
期刊：
影响因子：
8.3
通讯作者：
Dzau, VJ
中科院分区：
文献类型：
--
作者：
Horiuchi, M;Yamada, H;Dzau, VJ
据报道，细胞凋亡在血管重塑中起着关键作用。然而，血管平滑肌细胞(VSMCs)凋亡的细胞机制还不是很清楚。在这项研究中，我们重点研究了白介素1β转换酶(ICE)，这是一种诱导淋巴细胞和成纤维细胞凋亡的关键蛋白酶。我们观察到血清耗竭后大鼠主动脉VSMCs ICE mRNA的表达增加，12h达到高峰，然后逐渐下降。这与DNA片段化有关，DNA片段化是细胞凋亡的标志，也是细胞凋亡的形态变化。用ICE抑制剂N-(N-acetyl-tyrosinyl-valinyl-alaninyl)-3-amino-4-oxobutanoic酸(WAD-CHO)处理这些VSMC可减弱DNA片段化。在ICE mRNA表达增加之前，干扰素调节因子(IRF)-1的mRNA表达在血清去除后6h达到峰值，而IRF-2mRNA的表达在血清去除后3h迅速但短暂地下降，达到最低点。为了证明IRE-I和IRF-2的这种相互作用调节ICE的表达和诱导细胞凋亡，我们将IRE-I和IRF-2的反义寡核苷酸导入VSMC，检测ICE基因的表达和细胞凋亡的变化。IRF-1反义处理减轻ICE表达增加，减少细胞凋亡变化，而IRF-2反义处理增加ICE mRNA表达，促进细胞凋亡变化。综上所述，我们的结果表明，VSMCs中的血清生长因子缺失上调了IRE-I，下调了IRF-2，从而增加了ICE的表达，并诱导了细胞凋亡。
Apoptosis has been reported to play a pivotal role in vascular remodeling. However, cellular mechanisms of apoptosis in vascular smooth muscle cells (VSMCs) have not been well defined. In this study, we focused on interleukin-1 beta-converting enzyme (ICE), a key protease in the induction of apoptosis in lymphocytes and fibroblasts. We observed an increase in ICE mRNA expression in rat aortic VSMCs after serum depletion, with a peak at 12 hours and then a gradual decline. This was associated with DNA fragmentation, a hallmark of apoptosis and morphological changes of apoptosis. Treatment of these VSMCs with the ICE inhibitor N-(N-acetyl-tyrosinyl-valinyl-alaninyl)-3-amino-4-oxobutanoic acid (WAD-CHO) attenuated DNA fragmentation. The increased ICE mRNA expression was preceded by an increase in the mRNA expression of interferon regulatory factor (IRF)-1, peaking at 6 hours after serum removal, and a rapid but transient decrease in IRF-2 mRNA expression, reaching a nadir at 3 hours after serum depletion. To demonstrate that these reciprocal changes in IRE-I and IRF-2 regulated ICE expression and induced apoptosis, we transfected antisense oligonucleotides for IRE-I and IRF-2 into VSMCs and examined ICE mRNA expression and apoptotic changes. IRF-1 antisense pretreatment attenuated the increase in ICE expression and reduced apoptotic changes, whereas IRF-2 antisense treatment increased ICE mRNA expression and enhanced apoptotic changes. Taken together, our results suggest that serum growth factor depletion in VSMCs upregulates IRE-I and downregulates IRF-2, thereby increasing ICE expression and inducing apoptosis.