Heme oxygenase-1-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth
Heme oxygenase-1-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth
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DOI：
10.1182/blood.v99.12.4443
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发表时间：
2002-06-15
期刊：
影响因子：
20.3
通讯作者：
Durante, W
中科院分区：
文献类型：
--
作者：
Peyton, KJ;Reyna, SV;Durante, W
血管平滑肌细胞（SMC）通过血红素加氧酶（HO）催化血红素生成一氧化碳（CO）。在本研究中，我们发现，血清刺激血管平滑肌细胞HO-1信使RNA（mRNA）和蛋白水平的时间和浓度依赖性增加。血清对HO-1表达的诱导作用可被放线菌素D或放线菌酮抑制。此外，血清刺激HO活性，如通过培养基中胆红素浓度的增加所反映的。用血清刺激的DNA合成治疗血管SMC，并且这通过HO抑制剂锌和锡原卟啉-IX以及CO清除剂血红蛋白增强。铁螯合剂去铁胺对DNA合成无影响。然而，血管平滑肌细胞暴露于外源性CO抑制血清刺激的SMC增殖和视网膜母细胞瘤蛋白的磷酸化。此外，CO可使SMC阻滞于细胞周期的Gills转换期，并选择性地阻断血清刺激的cyclin A mRNA和蛋白的表达，而不影响cyclin D1和E的表达。CO还抑制血清刺激的细胞周期蛋白A相关激酶活性和细胞周期蛋白依赖性激酶2活性的激活。这些结果表明，血清刺激HO-1基因表达和CO合成。此外，他们表明，CO的行为在负反馈的方式，以抑制血管平滑肌细胞的生长，通过调节细胞周期机制的特定组件。血管有丝分裂原诱导CO合成的能力可能提供了一种新的机制，通过这种机制，这些药物调节细胞生长。(C)2002年，美国血液学会。
Vascular smooth muscle cells (SMCs) generate carbon monoxide (CO) via the catabolism of heme by the enzyme heme oxygenase (HO). In the present study, we found that serum stimulated a time- and concentration-dependent increase in the levels of HO-1 messenger RNA (mRNA) and protein in vascular SMCs. The induction of HO-1 expression by serum was inhibited by actinomycin D or cycloheximide. In addition, serum stimulated HO activity, as reflected by an increase in the concentration of bilirubin in the culture media. Treatment of vascular SMCs with serum stimulated DNA synthesis and this was potentiated by the HO inhibitors, zinc and tin protoporphyrin-IX as well as by the CO scavenger, hemoglobin. The iron chelator desferrioxamine had no effect on DNA synthesis. However, exposure of vascular SMCs to exogenous CO inhibited serum-stimulated SMC proliferation and the phosphorylation of retinoblastoma protein. In addition, CO arrested SMCs at the Gills transition phase of the cell cycle and selectively blocked the serum-stimulated expression of cyclin A mRNA and protein without affecting the expression of cyclin D1 and E. CO also inhibited the serum-stimulated activation of cyclin A-associated kinase activity and cyclin-dependent kinase 2 activity. These results demonstrate that serum stimulates HO-1 gene expression and CO synthesis. Furthermore, they show that CO acts in a negative feedback fashion to inhibit vascular SMC growth by regulating specific components of the cell cycle machinery. The capacity of vascular mitogens to induce CO synthesis may provide a novel mechanism by which these agents modulate cell growth. (C) 2002 by The American Society of Hematology.