Pharmacological preconditioning with tumor necrosis factor-α activates signal transducer and activator of transcription-3 at reperfusion without involving classic prosurvival kinases (Akt and extracellular signal-regulated kinase)
Pharmacological preconditioning with tumor necrosis factor-α activates signal transducer and activator of transcription-3 at reperfusion without involving classic prosurvival kinases (Akt and extracellular signal-regulated kinase)
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DOI：
10.1161/circulationaha.105.581058
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发表时间：
2005-12-20
期刊：
影响因子：
37.8
通讯作者：
Opie, LH
中科院分区：
文献类型：
--
作者：
Lecour, S;Suleman, N;Opie, LH
背景 - 我们先前报道肿瘤坏死因子 -α（TNF -α）能够以剂量和时间依赖的方式模拟经典的缺血预处理（IPC）。因为TNF -α激活信号转导和转录激活因子 - 3（STAT - 3），我们假设TNF -α诱导的预处理在再灌注早期需要STAT - 3的磷酸化，而不涉及经典的促存活激酶Akt和细胞外信号调节激酶（Erk）1/2。
方法和结果 - 通过IPC或低剂量TNF -α（0.5 ng/mL）对分离的缺血/再灌注大鼠心脏进行预处理。蛋白质印迹分析证实，再灌注5分钟后IPC使Akt和Erk 1/2磷酸化（与对照组相比，Akt增加34 ± 6%，Erk增加105 ± 28%；P < 0.01）。再灌注早期磷脂酰肌醇3 - 激酶/Akt抑制（渥曼青霉素）或丝裂原活化蛋白激酶 - Erk 1/2激酶抑制（PD - 98059）消除了IPC的梗死面积缩小效应。相反，TNF -α预处理并未使这些激酶磷酸化（与对照组相比，Akt增加7 ± 7%，Erk增加17 ± 14%；P = 无统计学意义）。渥曼青霉素和PD - 98059均未抑制TNF -α介导的心脏保护作用。然而，TNF -α和IPC都使STAT - 3以及促凋亡蛋白Bcl - 2细胞死亡拮抗剂（BAD）磷酸化（TNF -α使STAT - 3增加58 ± 17%，IPC使STAT - 3增加68 ± 12%；TNF -α使BAD增加75 ± 8%，IPC使BAD增加205 ± 20%；与对照组相比，P < 0.01），从而激活前者并使后者失活。STAT - 3抑制剂AG 490消除了两种预处理刺激的心脏保护作用和BAD磷酸化。
结论 - 在再灌注早期阶段，经典促存活激酶（Akt和Erk 1/2）的激活对于TNF -α诱导的预处理不是必需的。我们表明存在一种替代的保护途径，该途径涉及在再灌注时对TNF -α和经典IPC都有特异性的STAT - 3激活。这种新的促存活途径可能具有潜在的治疗意义。
Background - We previously reported that tumor necrosis-factor-alpha (TNF-alpha) can mimic classic ischemic preconditioning (IPC) in a dose- and time-dependent manner. Because TNF-alpha activates the signal transducer and activator of transcription-3 (STAT-3), we hypothesized that TNF-alpha-induced preconditioning requires phosphorylation of STAT-3 rather than involving the classic prosurvival kinases, Akt and extracellular signal - regulated kinase (Erk) 1/2, during early reperfusion.Methods and Results - Isolated, ischemic/reperfused rat hearts were preconditioned by either IPC or low-dose TNF-alpha (0.5 ng/mL). Western blot analysis confirmed that IPC phosphorylated Akt and Erk 1/2 after 5 minutes of reperfusion ( Akt increased by 34 +/- 6% and Erk, by 105 +/- 28% versus control; P < 0.01). Phosphatidylinositol 3-kinase/Akt inhibition ( wortmannin) or mitogen-activated protein kinase - Erk 1/2 kinase inhibition (PD-98059) during early reperfusion abolished the infarct-sparing effect of IPC. In contrast, TNF-alpha preconditioning did not phosphorylate these kinases (Akt increased by 7 +/- 7% and Erk, by 17 +/- 14% versus control; P = NS). Neither wortmannin nor PD-98059 inhibited TNF-alpha-mediated cardioprotection. However, TNF-alpha and IPC both phosphorylated STAT- 3 and the proapoptotic protein Bcl-2 antagonist of cell death ( BAD) ( STAT- 3 increased by 58 +/- 17% with TNF-alpha or by 68 +/- 12% with IPC; BAD increased by 75 +/- 8% with TNF-alpha or by 205 +/- 20% with IPC; P < 0.01 versus control), thereby activating the former and inactivating the latter. The STAT- 3 inhibitor AG 490 abolished cardioprotection and BAD phosphorylation with both preconditioning stimuli.Conclusions - Activation of the classic prosurvival kinases ( Akt and Erk 1/2) is not essential for TNF-alpha-induced preconditioning in the early reperfusion phase. We show the existence of an alternative protective pathway that involves STAT- 3 activation specifically at reperfusion in response to both TNF-alpha and classic IPC. This novel prosurvival pathway may have potential therapeutic significance.