New targets of urocortin-mediated cardioprotection.
New targets of urocortin-mediated cardioprotection.
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DOI：
10.1677/jme-09-0148
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发表时间：
2010-08
影响因子：
3.5
通讯作者：
Stephanou A
中科院分区：
文献类型：
--
作者：
Barry SP;Lawrence KM;McCormick J;Soond SM;Hubank M;Eaton S;Sivarajah A;Scarabelli TM;Knight RA;Thiemermann C;Latchman DS;Townsend PA;Stephanou A
尿皮质素 (UCN) 激素 UCN1 和 UCN2 先前已被证明可对心肌缺血/再灌注 (I/R) 损伤提供显着的保护作用；然而，人们对其作用背后的分子机制知之甚少。为了进一步确定 UCN 的转录作用（支撑其心脏保护活性），使用 I/R 损伤的体内大鼠冠状动脉闭塞模型进行了微阵列分析。再灌注开始前输注 UCN1 或 UCN2 分别导致 66 和 141 个基因的差异调节，其中大部分此前未曾描述过。功能分析表明，UCN调控基因参与广泛的生物反应，包括细胞死亡（例如X连锁凋亡蛋白抑制剂）、氧化应激（例如核因子红细胞衍生2相关因子1/核因子红细胞衍生2样1）和代谢（例如Prkaa2/AMPK）。此外，UCN1和UCN2被发现可以调节许多参与G蛋白偶联受体（GPCR）信号传导的基因的表达，包括Rac2、Gnb1、Dab2ip（AIP1）、Ralgds、Rnd3、Rap1a和PKA，从而揭示了CRH受体下游先前未被识别的信号传导中间体。此外，其中一些 GPCR 相关基因先前已被证明参与丝裂原激活蛋白激酶 (MAPK) 激活，表明 CRH 受体与 MAPK 诱导之间存在联系。此外，我们还发现 UCN1 和 UCN2 均显着减少心肌梗塞后的自由基损伤，并且 UCN 基因特征与抗氧化 tempol 基因特征的比较显示出显着的重叠。这些数据揭示了 UCN 诱导的新基因表达变化，这将作为进一步了解其在正常生理和心脏保护中的作用机制的平台。
The urocortin (UCN) hormones UCN1 and UCN2 have been shown previously to confer significant protection against myocardial ischaemia/reperfusion (I/R) injury; however, the molecular mechanisms underlying their action are poorly understood. To further define the transcriptional effect of UCNs that underpins their cardioprotective activity, a microarray analysis was carried out using an in vivo rat coronary occlusion model of I/R injury. Infusion of UCN1 or UCN2 before the onset of reperfusion resulted in the differential regulation of 66 and 141 genes respectively, the majority of which have not been described previously. Functional analysis demonstrated that UCN-regulated genes are involved in a wide range of biological responses, including cell death (e.g. X-linked inhibitor of apoptosis protein), oxidative stress (e.g. nuclear factor erythroid derived 2-related factor 1/nuclear factor erythroid derived 2-like 1) and metabolism (e.g. Prkaa2/AMPK). In addition, both UCN1 and UCN2 were found to modulate the expression of a host of genes involved in G-protein-coupled receptor (GPCR) signalling including Rac2, Gnb1, Dab2ip (AIP1), Ralgds, Rnd3, Rap1a and PKA, thereby revealing previously unrecognised signalling intermediates downstream of CRH receptors. Moreover, several of these GPCR-related genes have been shown previously to be involved in mitogen-activated protein kinase (MAPK) activation, suggesting a link between CRH receptors and induction of MAPKs. In addition, we have shown that both UCN1 and UCN2 significantly reduce free radical damage following myocardial infarction, and comparison of the UCN gene signatures with that of the anti-oxidant tempol revealed a significant overlap. These data uncover novel gene expression changes induced by UCNs, which will serve as a platform to further understand their mechanism of action in normal physiology and cardioprotection.