Pradervand Sylvain, Yasukawa Hideo, Muller Olivier G, Kjekshus Harald, Nakamura Tomoyuki, St Amand Tara R, Yajima Toshitaka, Matsumura Kiyoyuki, Duplain Hervé, Iwatate Mitsuo, Woodard Sarah, Pedrazzini Thierry, Ross John, Firsov Dmitri, Rossier Bernard C, Hoshijima Masahiko, Chien Kenneth R
UCSD Institute of Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
EMBO J. 2004 Nov 10;23(22):4517-25. doi: 10.1038/sj.emboj.7600454. Epub 2004 Oct 28.
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.
白细胞介素-6细胞因子通过gp130受体途径发挥作用，在减轻机械应激或缺血诱导的心脏损伤以及促进随后的心脏适应性重塑中起关键作用。我们现已确定富含脯氨酸的小重复蛋白（SPRR）1A和2A是gp130信号传导的下游靶点，在响应生物力学/缺血应激的心肌细胞中被强烈诱导。在gp130心肌细胞特异性敲除小鼠中，SPRR1A和2A的上调明显减少。在心肌细胞中，MEK1/2抑制剂可阻止gp130细胞因子上调SPRR1A。此外，CT-1刺激后观察到NF-IL6（C/EBPβ）和c-Jun与SPRR1A启动子的结合。组织学分析显示，压力超负荷机械应激后SPRR1A的诱导仅限于散在坏死病变周围的心肌细胞。在心肌梗死后的大鼠心脏中也发现了类似的表达模式。体外和体内异位过表达SPRR1A均可保护心肌细胞免受缺血损伤。因此，本研究确定SPRR1A是心肌细胞中gp130细胞因子一种新的应激诱导下游介质，并证明了其对缺血应激的心脏保护作用。
