Morita T, Perrella M A, Lee M E, Kourembanas S
Department of Pediatrics, Harvard Medical School, Boston, MA.
Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1475-9. doi: 10.1073/pnas.92.5.1475.
Carbon monoxide (CO) is a product of the enzyme heme oxygenase (HO; EC 1.14.99.3). In vascular smooth muscle cells, exogenously administered CO increases cyclic guanosine 3',5'-monophosphate (cGMP), which is an important regulator of vessel tone. We report here that smooth muscle cells produce CO via HO and that it regulates cGMP levels in these cells. Hypoxia, which has profound effects on vessel tone, significantly increased the transcriptional rate of the HO-1 gene resulting in corresponding increases of its mRNA and HO enzymatic activity. In addition, under the same conditions, rat aortic and pulmonary artery smooth muscle cells accumulated high levels of cGMP following a similar time course to that of HO-1 production. The increased accumulation of cGMP in smooth muscle cells required the enzymatic activity of HO, since it was abolished by a specific HO inhibitor, tin protoporphyrin. In contrast, N omega-nitro-L-arginine, a potent inhibitor of nitric oxide (NO) synthesis, had no effect on cGMP produced by smooth muscle cells, indicating that NO is not responsible for the activation of guanylyl cyclase in this setting. Furthermore, conditioned medium from hypoxic smooth muscle cells stimulated cGMP production in recipient cells and this stimulation was completely inhibited by tin protoporphyrin or hemoglobin, an inhibitor of CO production and a scavenger of CO, respectively. This report shows that HO-1 is expressed by vascular smooth muscle cells and that its product, CO, may regulate vascular tone under physiologic and pathophysiologic (such as hypoxic) conditions.
一氧化碳（CO）是血红素加氧酶（HO；EC 1.14.99.3）的产物。在血管平滑肌细胞中，外源性给予的CO可增加环磷酸鸟苷（cGMP），而cGMP是血管张力的重要调节因子。我们在此报告，平滑肌细胞通过HO产生CO，并且它调节这些细胞中的cGMP水平。对血管张力有深远影响的缺氧显著增加了HO-1基因的转录速率，导致其mRNA和HO酶活性相应增加。此外，在相同条件下，大鼠主动脉和肺动脉平滑肌细胞中cGMP的积累水平与HO-1产生的时间进程相似。平滑肌细胞中cGMP积累的增加需要HO的酶活性，因为它被一种特异性HO抑制剂锡原卟啉所消除。相反，一氧化氮（NO）合成的强效抑制剂Nω-硝基-L-精氨酸对平滑肌细胞产生的cGMP没有影响，这表明在这种情况下NO不是激活鸟苷酸环化酶的原因。此外，缺氧平滑肌细胞的条件培养基刺激受体细胞中cGMP的产生，并且这种刺激分别被锡原卟啉或血红蛋白完全抑制，血红蛋白是CO产生的抑制剂和CO的清除剂。本报告表明，HO-1由血管平滑肌细胞表达，并且其产物CO可能在生理和病理生理（如缺氧）条件下调节血管张力。
