cAMP induces heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle
cAMP induces heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle
复制标题
DOI：
10.1152/ajpheart.1997.273.1.h317
复制
发表时间：
1997-07-01
影响因子：
4.8
通讯作者：
Schafer, AI
中科院分区：
文献类型：
--
作者：
Durante, W;Christodoulides, N;Schafer, AI
最近的研究表明，血管平滑肌细胞通过血红素加氧酶（HO）的作用产生一氧化碳（GO）。由于腺苷3 '，5'-环磷酸（cAMP）是调节血管细胞功能的重要细胞内信号分子，我们研究了该第二信使是否调节大鼠主动脉平滑肌细胞HO的表达和CO的产生。用膜渗透性cAMP衍生物二丁酰cAMP或增加细胞内cAMP水平的化合物（异丙肾上腺素和毛喉素）处理平滑肌细胞，导致HO-1 mRNA和蛋白质水平呈浓度和时间依赖性增加，而HO-2的表达保持不变。放线菌素D和放线菌酮均能阻断HO-1 mRNA和蛋白的基础表达，并阻止cAMP介导的HO-1诱导。孵育的血小板与cAMP处理的平滑肌细胞导致血小板cGMP浓度的显着增加，这是部分逆转的一氧化氮合酶抑制剂N-G-单甲基-L-精氨酸或HO阻断剂锌原卟啉-IX的平滑肌细胞的治疗。然而，将这两种抑制剂组合添加到cAMP处理的平滑肌细胞中或将CO和NO清除剂血红蛋白添加到血小板中完全阻断了对血小板cGMP水平的刺激作用。这些结果表明，cAMP诱导HO-1基因的表达，并刺激血管平滑肌细胞中CO和NO的形成。cAMP诱导平滑肌细胞合成鸟苷酸环化酶刺激性CO的能力可能代表了这种核苷酸调节血管张力的新机制。
Recent studies indicate that vascular smooth muscle cells generate carbon monoxide (GO) via the action of heme oxygenase (HO). Because adenosine 3',5'-cyclic monophosphate (cAMP) is an important intracellular signaling molecule in the regulation of vascular cell function, we examined whether this second messenger modulates the expression of HO and the production of CO by rat aortic smooth muscle cells. Treatment of smooth muscle cells with the membrane-permeable cAMP derivative dibutyryl cAMP or with compounds that increase intracellular cAMP levels (isoproterenol and forskolin) resulted in a concentration- and time-dependent increase in the levels of HO-1 mRNA and protein, whereas the expression of HO-2 remained unchanged. Both actinomycin D and cycloheximide blocked the basal expression of HO-1 mRNA and protein and prevented the cAMP-mediated induction of HO-1. Incubation of platelets with cAMP-treated smooth muscle cells resulted in a significant increase in platelet cGMP concentration that was partially reversed by treatment of smooth muscle cells with the nitric oxide synthase inhibitor N-G-monomethyl-L-arginine or the HO blocker zinc protoporphyrin-IX. However, the combined addition of these two inhibitors to cAMP-treated smooth muscle cells or the addition of the CO and NO scavenger hemoglobin to platelets completely blocked the stimulatory effect on platelet cGMP levels. These results demonstrate that cAMP induces the expression of the HO-1 gene and stimulates the formation of CO and NO in vascular smooth muscle cells. The capacity of cAMP to induce the synthesis of guanylate cyclase-stimulatory CO from smooth muscle cells may represent a novel mechanism by which this nucleotide regulates vascular tone.