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

• Type of Material: Article
• Authors: Qiang Li, University of California Los Angeles; Ping Wang, University of California Los Angeles; Keqiang Ye, Emory University; Hua Cai, University of California Los Angeles
• Language: English
• Date: 2015-01-20
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: NATIONAL ACADEMY OF SCIENCES
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1420695112
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 112
• Issue: 3
• Start Page: 899
• End Page: 904
• Grant/Funding Information: This study was supported by NIH National Heart, Lung and Blood Institute Grants HL077440 (to H.C.), HL088975 (to H.C.), HL108701 (to H.C. and David G. Harrison), and HL119968 (to H.C.); American Heart Association Established Investigator Award 12EIA8990025 (to H.C.); and American Heart Association Postdoctoral Fellowship Award 14POST20380966 (to Q.L.).
• Keywords: cardioprotection; GENE; RECEPTOR; APOPTOSIS; FEEDFORWARD MECHANISM; Science & Technology - Other Topics; MYOCARDIAL-INFARCTION; SIAH; PATHWAY; PROTEOLYSIS; RING DOMAIN; Science & Technology; nitric oxide; TUMORIGENESIS; E3 UBIQUITIN LIGASES; netrin-1; Multidisciplinary Sciences; DCC
• Research Categories: Biology, Genetics; Health Sciences, Oncology

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.