Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410008, PR China.
Cardiovasc Res. 2013 Jul 1;99(1):92-101. doi: 10.1093/cvr/cvt085. Epub 2013 Apr 16.
Nucleolin plays important roles in a variety of cellular processes. In this study, we aimed to investigate the role of nucleolin in cardiac ischaemia-reperfusion (I-R) injury.
We investigated the expression pattern of nucleolin in hearts subjected to I-R, or neonatal rat cardiomyocytes subjected to hypoxia-re-oxygenation. We found that nucleolin expression was significantly down-regulated and the cleaved protein was present, both in vivo and in vitro. Gene transfection and RNA interference approaches were employed in cardiomyocytes to investigate the function of nucleolin. Over-expression of nucleolin was cytoprotective, whereas nucleolin ablation enhanced both hypoxia- and H₂O₂-induced cardiomyocyte death. Furthermore, transgenic mice with cardiac-specific over-expression of nucleolin were resistant to I-R injury as indicated by decreased cellular necrosis and decreased infarct size. The cardio-protective roles of nucleolin in cardiomyocytes, are attributable to the interaction of nucleolin with the mRNA of heat shock protein 32 (Hsp32), resulting in an increase of Hsp32 mRNA stability, and subsequent up-regulation of Hsp32 expression. The selective Hsp32 inhibitor, zinc protoporphyrin-IX, abrograted the cardiac protection mediated by nucleolin.
This study has demonstrated that nucleolin is involved in the regulation of I-R-induced cardiac injury and dysfunction via the regulation of Hsp32, and may be a novel therapeutic target for ischaemic heart diseases.
核仁素在多种细胞过程中发挥重要作用。本研究旨在探讨核仁素在心肌缺血再灌注（I-R）损伤中的作用。
我们研究了核仁素在 I-R 心脏或缺氧-复氧的新生大鼠心肌细胞中的表达模式。我们发现，核仁素表达明显下调，体内和体外均存在裂解蛋白。我们在心肌细胞中采用基因转染和 RNA 干扰方法研究核仁素的功能。核仁素的过表达具有细胞保护作用，而核仁素缺失则增强了缺氧和 H₂O₂诱导的心肌细胞死亡。此外，心脏特异性过表达核仁素的转基因小鼠对 I-R 损伤具有抗性，表现为细胞坏死减少和梗死面积减小。核仁素在心肌细胞中的心脏保护作用归因于核仁素与热休克蛋白 32（Hsp32）mRNA 的相互作用，导致 Hsp32 mRNA 稳定性增加，随后 Hsp32 表达上调。选择性 Hsp32 抑制剂锌原卟啉-IX 阻断了核仁素介导的心脏保护作用。
本研究表明，核仁素通过调节 Hsp32 参与调节 I-R 诱导的心脏损伤和功能障碍，可能是缺血性心脏病的新治疗靶点。
