Nitric oxide stimulates PC12 cell proliferation via cGMP and inhibits at higher concentrations mainly via energy depletion
Nitric oxide stimulates PC12 cell proliferation via cGMP and inhibits at higher concentrations mainly via energy depletion
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DOI：
10.1016/j.niox.2005.10.002
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发表时间：
2006-05-01
影响因子：
3.9
通讯作者：
Brown, GC
中科院分区：
文献类型：
--
作者：
Bal-Price, A;Gartlon, J;Brown, GC
我们研究了来自 NO 供体 (DETA/NO) 的一氧化氮 (NO) 调节嗜铬细胞瘤 PC12 细胞增殖的机制。 NO供体在低浓度下刺激增殖，但在较高浓度下可逆且完全抑制增殖。增殖的刺激（而不是抑制）显然是由于NO刺激可溶性鸟苷酸环化酶产生cGMP，因为它被特定的环化酶抑制剂（ODQ）阻止，并被细胞可渗透形式的cGMP复制。MEK激酶或聚（ADP-核糖）聚合酶的抑制剂不能逆转NO诱导的细胞停滞， 或通过绕过核糖核苷酸还原酶或鸟氨酸脱羧酶抑制的治疗。 DETA/NO 的细胞抑制浓度强烈抑制 PC 12 细胞的呼吸，并且特定的呼吸抑制剂（鱼藤酮.. myxothiazol 或叠氮化物）导致完全细胞抑制。尿苷和丙酮酸可逆转特定呼吸抑制剂诱导的细胞抑制，但不能逆转 DETA/NO 诱导的细胞抑制。然而，尿苷、丙酮酸和N-乙酰基-半胱氨酸的组合确实逆转了DETA/NO诱导的细胞停滞。 DETA/NO 强烈且渐进地抑制通过葡萄糖消耗、乳酸产生和 ATP 水平测量的糖酵解，并且特定的糖酵解抑制剂（5 mM 2-脱氧-D-葡萄糖）导致完全细胞停滞。我们的结果表明，低浓度的 NO 通过 cGMP 增加细胞增殖，而高浓度的 NO 通过抑制糖酵解和呼吸来阻止增殖，导致能量消耗。 (c) 2005 Elsevier Inc. 保留所有权利。
We investigated the mechanisms by which nitric oxide (NO) from an NO donor (DETA/NO) regulates proliferation of pheochromocytoma PC12 cells. The NO donor stimulated proliferation at low concentrations, but reversibly and completely inhibited proliferation at higher concentrations. The stimulation (but not the inhibition) of proliferation was apparently due to NO stimulation of soluble guanylate cyclase to produce cGMP, as it was prevented by a specific cyclase inhibitor (ODQ), and replicated by a cell-permeable form of cGMP, The NO-induced cytostasis was not reversed by inhibitors of MEK kinase or poly(ADP-ribose)polymerase, or by treatments that bypass inhibition of ribonucleotide reductase or ornithine decarboxylase. Cytostatic concentrations of DETA/NO strongly inhibited respiration of PC 12 cells, and specific respiratory inhibitors (rotenone.. myxothiazol, or azide) caused complete cytostasis. Uridine and pyruvate reversed the cytostasis induced by the specific respiratory inhibitors, but not that induced by DETA/NO. However, the combination Of Uridine, pyruvate, and N-acetyl-cysteine did reverse DETA/NO-induced cytostasis. DETA/NO strongly and progressively inhibited glycolysis measured by glucose consumption, lactate production, and ATP level, and a specific glycolytic inhibitor (5 mM 2-deoxy-D-glucose)caused complete cytostasis. Our results indicate that NO at low concentrations increases cell proliferation via cGMP, while high concentrations of NO block proliferation via inhibition of both glycolysis and respiration, causing energy depletion. (c) 2005 Elsevier Inc. All rights reserved.