Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells
Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells
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DOI：
10.1089/152308602753666280
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发表时间：
2002-04-01
影响因子：
6.6
通讯作者：
Motterlini, R
中科院分区：
文献类型：
--
作者：
Dulak, J;Józkowicz, A;Motterlini, R
缺氧、细胞因子和一氧化氮（NO）刺激血管内皮生长因子（VEGF）的生成，诱导血管组织中血红素氧化酶-1 （HO-1）的表达。HO-1将血红素降解为一氧化碳（CO）、铁和胆绿素，后者被胆绿素还原酶还原为胆红素。在本研究中，我们研究了HO-1在大鼠血管平滑肌细胞（VSMC）中调节VEGF合成的作用。在细胞因子刺激的VSMC中，抑制NO的产生显著但不完全地降低了VEGF的释放。相比之下，锡原卟啉IX （SnPPIX）对HO活性的抑制完全阻止了细胞因子诱导的VEGF的增加，尽管增加了细胞内NO的合成。血红素刺激HO-I活性可促进VEGF生成；阻断HO通路可消除这种作用。同样，SnPPIX可下调缺氧诱导的VEGF合成，而NO合成酶抑制剂则无此作用。为了进一步阐明HO-1在观察到的效应中的直接参与，我们产生了过表达HO-1基因的转染细胞。值得注意的是，这些细胞比转染了对照基因的细胞合成了更多的VEGF蛋白。HO-1产物中胆绿素和胆红素对VEGF的合成无影响，而铁离子对VEGF的合成有抑制作用。细胞暴露于1%的一氧化碳导致VEGF在基础水平上显著积累（增加20倍）。我们的数据表明，在常氧和缺氧条件下，HO-1活性都会影响VSMC中VEGF的生成。在血红素降解的过程中，CO和铁分别是VEGF合成的诱导剂和抑制剂，这些数据表明HO副产物可能对VEGF的产生有差异调节。
Hypoxia, cytokines, and nitric oxide (NO) stimulate the generation of vascular endothelial growth factor (VEGF) and induce heme oxygenase-1 (HO-1) expression in vascular tissue. HO-1 degrades heme to carbon monoxide (CO), iron, and biliverdin, the latter being reduced to bilirubin by biliverdin reductase. In the present study, we investigated the role of HO-1 in the modulation of VEGF synthesis in rat vascular smooth muscle cells (VSMC). In VSMC stimulated with cytokines, inhibition of NO production significantly, but not completely, reduced VEGF release. In contrast, inhibition of HO activity by tin protoporphyrin IX (SnPPIX) totally prevented cytokine-induced increase in VEGF, despite an augmented synthesis of intracellular NO. Stimulation of HO-I activity by hemin enhanced VEGF production; this effect was abrogated by blockade of the HO pathway. Similarly, VEGF synthesis induced by hypoxia was down-regulated by SnPPIX, but not by inhibitors of NO synthase. To elucidate further a direct involvement of HO-1 in the observed effects, we generated transfected cells that overexpressed the HO-I gene. Notably, these cells synthesized significantly more VEGF protein than cells transfected with a control gene. Among the products of HO-1, biliverdin and bilirubin showed no effect, whereas iron ions inhibited VEGF synthesis. Exposure of cells to 1% CO resulted in a marked accumulation of VEGF (20-fold increase) over the basal level. Our data indicate that HO-1 activity influences the generation of VEGF in VSMC in both normoxic and hypoxic conditions. As CO and iron, respectively the inducer and the inhibitor of VEGF synthesis, are concomitantly produced during the degradation of heme, these data indicate that HO by-products may differentially modulate VEGF production.