Small proline-rich protein 1A is a gp130 pathway- and stress-inducible cardioprotective protein
Small proline-rich protein 1A is a gp130 pathway- and stress-inducible cardioprotective protein
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DOI：
10.1038/sj.emboj.7600454
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发表时间：
2004-11-10
期刊：
影响因子：
11.4
通讯作者：
Chien, KR
中科院分区：
文献类型：
--
作者：
Pradervand, S;Yasukawa, H;Chien, KR
白细胞介素-6细胞因子通过gp 130受体途径发挥作用，在减少机械应力或缺血引起的心脏损伤和促进随后的心脏适应性重塑中发挥关键作用。我们现在已经确定了富含脯氨酸的小重复序列蛋白（SPRR）1A和2A作为gp 130信号传导的下游靶点，这些靶点在心肌细胞对生物力学/缺血应激的反应中被强烈诱导。在gp 130心肌细胞限制性基因敲除小鼠中，SPRR 1A和2A的上调显著降低。在心肌细胞中，MEK 1/2抑制剂阻止了gp 130细胞因子对SPRR 1A的上调。此外，在CT-1刺激后观察到NF-IL 6（C/EBP β）和c-Jun与SPRR 1A启动子的结合。组织学分析表明，SPRR 1A诱导后的机械应力的压力过载被限制在周围的肌细胞碎片坏死病变。一个类似的表达模式被发现在梗死后大鼠心脏。在体外和体内异位过表达SPRR 1A保护心肌细胞免受缺血性损伤。因此，这项研究确定SPRR 1A作为一种新的应激诱导的下游介导的gp 130细胞因子在心肌细胞和文件的心脏保护作用，对缺血性应激。
The interleukin-6 cytokines, acting via gp130 receptor pathways, play a pivotal role in the reduction of cardiac injury induced by mechanical stress or ischemia and in promoting subsequent adaptive remodeling of the heart. We have now identified the small proline-rich repeat proteins (SPRR) 1A and 2A as downstream targets of gp130 signaling that are strongly induced in cardiomyocytes responding to biomechanical/ischemic stress. Upregulation of SPRR1A and 2A was markedly reduced in the gp130 cardiomyocyte-restricted knockout mice. In cardiomyocytes, MEK1/2 inhibitors prevented SPRR1A upregulation by gp130 cytokines. Furthermore, binding of NF-IL6 (C/EBPbeta) and c-Jun to the SPRR1A promoter was observed after CT-1 stimulation. Histological analysis revealed that SPRR1A induction after mechanical stress of pressure overload was restricted to myocytes surrounding piecemeal necrotic lesions. A similar expression pattern was found in postinfarcted rat hearts. Both in vitro and in vivo ectopic overexpression of SPRR1A protected cardiomyocytes against ischemic injury. Thus, this study identifies SPRR1A as a novel stress-inducible downstream mediator of gp130 cytokines in cardiomyocytes and documents its cardioprotective effect against ischemic stress.