期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：3
页码：899-904
DOI：10.1073/pnas.1420695112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceTherapies for myocardial infarction consequent to ischemia/reperfusion injury (I/R) have been lacking. The netrin-1 receptor deleted in colorectal cancer (DCC) mediates netrin-1-dependent cardioprotective signaling. It is anticipated that any means of augmenting DCC signaling may induce cardioprotection on its own and enhance netrin-1/NO-dependent cardioprotection. The present study identifies a novel mechanism by which NO upregulates DCC abundance. NO inhibits seven in absentia homolog (SIAH), an E3 ubiquitin ligase that suppresses DCC. Inhibition of SIAH by in vivo RNA interference markedly reduces infarct size to improve cardiac function that was determined by echocardiography. Combined with netrin-1 perfusion, it further potentiated netrin-1's cardioprotective effect. SIAH may therefore serve as a novel therapeutic target for myocardial infarction, particularly those suffering from cardiac I/R injury. Deleted in colorectal cancer (DCC), a large transmembrane receptor of netrin-1, is critical for mediating netrin-1's cardioprotective function. In the present study we investigated novel mechanisms underlying netrin-1-induced, rapid, and feed-forward up-regulation of DCC, which is believed to sustain nitric oxide (NO) production to potentiate cardioprotection. Intriguingly, NO markedly reduced expression of the E3 ubiquitin ligase seven in absentia homolog (SIAH) that is specific for regulation of protesome-dependent DCC degradation, resulting in accumulation of DCC. The two SIAH isoforms compensate for each other when one is repressed; inhibition of both SIAH1 and SIAH2 using combined siRNAs significantly reduced infarct size while improving cardiac function after ischemia/reperfusion injury of the heart. This effect was absent in DCC-deficient mice. Moreover, in vivo RNAi inhibition of SIAH1/2 further augmented netrin-1's cardioprotective function. In summary, these data identify a novel therapeutic target of SIAH in facilitating NO/netrin-1-dependent cardioprotection, using the DCC receptor. Combination of netrin-1 and SIAH RNAi may prove to be a substantially effective therapy for myocardial infarction.
