Central role of SIAH inhibition in DCC-dependent cardioprotection provoked by netrin-1/NO.

Abstract

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.

• Authors: Qiang Li, Ping Wang, Keqiang Ye, Hua Cai
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 3 Pg. 899-904 (Jan 20 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25561546 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DCC Receptor
• Dcc protein, mouse
• NTN1 protein, human
• Nerve Growth Factors
• Ntn1 protein, mouse
• Nuclear Proteins
• Receptors, Cell Surface
• Tumor Suppressor Proteins
• Netrin-1
• Nitric Oxide
• Ubiquitin-Protein Ligases
• seven in absentia proteins

Topics

• Animals
• DCC Receptor
• HEK293 Cells
• Heart (physiology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (prevention & control)
• Nerve Growth Factors (physiology)
• Netrin-1
• Nitric Oxide (physiology)
• Nuclear Proteins (antagonists & inhibitors)
• Receptors, Cell Surface (genetics, physiology)
• Tumor Suppressor Proteins (genetics, physiology)
• Ubiquitin-Protein Ligases (antagonists & inhibitors)