PTPIP51 regulates mouse cardiac ischemia/reperfusion through mediating the mitochondria-SR junction.
PTPIP51 regulates mouse cardiac ischemia/reperfusion through mediating the mitochondria-SR junction.
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PTPIP51通过介导线粒体-SR连接调节小鼠心脏缺血/再灌注
DOI：
10.1038/srep45379
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发表时间：
2017-03-27
影响因子：
4.6
通讯作者：
Zheng M
中科院分区：
文献类型：
--
作者：
Qiao X;Jia S;Ye J;Fang X;Zhang C;Cao Y;Xu C;Zhao L;Zhu Y;Wang L;Zheng M
蛋白酪氨酸磷酸酶相互作用蛋白51（PTPIP 51）参与多种细胞过程，并且PTPIP 51的功能障碍与诸如癌症和神经退行性病症的疾病有关。然而，没有功能证据表明PTPIP 51在心脏中的生理或病理作用。因此，我们研究了PTPIP 51在调节心脏功能中的作用和机制。我们发现PTPIP 51在缺血/再灌注心脏中显著上调。通过腺病毒介导的PTPIP 51的过表达上调显著增加了心肌-肌浆网（SR）的接触，通过线粒体Ca 2+单向转运体从SR释放增加线粒体Ca 2+摄取。抑制或敲低线粒体Ca 2+单向转运体可逆转PTPIP 51介导的线粒体Ca 2+增加，并保护心肌细胞免受PTPIP 51介导的凋亡。更重要的是，心脏特异性敲低PTPIP 51大大减少了心肌梗死面积和缺血/再灌注后的心脏损伤。我们的研究确定了一个新的和必不可少的功能，PTPIP 51在心脏缺血/再灌注过程中，通过介导的ERA-SR接触。下调PTPIP 51可改善缺血/再灌注损伤后的心功能，提示PTPIP 51可作为缺血性心脏病的治疗靶点。
Protein tyrosine phosphatase interacting protein 51 (PTPIP51) participates in multiple cellular processes, and dysfunction of PTPIP51 is implicated in diseases such as cancer and neurodegenerative disorders. However, there is no functional evidence showing the physiological or pathological roles of PTPIP51 in the heart. We have therefore investigated the role and mechanisms of PTPIP51 in regulating cardiac function. We found that PTPIP51 was markedly upregulated in ischemia/reperfusion heart. Upregulation of PTPIP51 by adenovirus-mediated overexpression markedly increased the contact of mitochondria-sarcoplasmic reticulum (SR), elevated mitochondrial Ca2+uptake from SR release through mitochondrial Ca2+uniporter. Inhibition or knockdown of mitochondrial Ca2+uniporter reversed PTPIP51-mediated increase of mitochondrial Ca2+and protected cardiomyocytes against PTPIP51-mediated apoptosis. More importantly, cardiac specific knockdown of PTPIP51 largely reduced myocardium infarction size and heart injury after ischemia/reperfusion. Our study defines a novel and essential function of PTPIP51 in the cardiac ischemia/reperfusion process by mediating mitochondria-SR contact. Downregulation of PTPIP51 improves heart function after ischemia/reperfusion injury, suggesting PTPIP51 as a therapeutic target for ischemic heart diseases.