Loss of the miR-144/451 cluster impairs ischaemic preconditioning-mediated cardioprotection by targeting Rac-1
Open Access
- 21 February 2012
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 94 (2), 379-390
- https://doi.org/10.1093/cvr/cvs096
Abstract
While a wealth of data has uncovered distinct microRNA (miR) expression alterations in hypertrophic and ischaemic/reperfused (I/R) hearts, little is known about miR regulation and response to ischaemic preconditioning (IPC). We analysed miRs in murine hearts preconditioned with six cycles of 4 min ischaemia via coronary artery occlusion, followed by 4 min reperfusion in vivo. Both miRs within the miR-144/451 cluster were the most elevated among a cohort of 21 dysregulated miRs in preconditioned hearts, compared with shams. To investigate the significance of this finding, we examined IPC-mediated cardioprotection within a miR-144/451-knockout (KO) mouse model. Wild-type (WT) hearts exposed to IPC followed by I/R (30 min/24 h) showed a smaller infarction size compared with mice treated with I/R alone. In contrast, IPC failed to protect miR-144/451-KO hearts against infarct caused by I/R treatment. Thus, the miR-144/451 cluster is required for IPC-elicited cardioprotection. Rac-1, a key component of NADPH oxidase, was mostly up-regulated in KO hearts among three bona fide targets (Rac-1, 14-3-3ζ, and CUGBP2) for both miR-144 and miR-451. Accordingly, reactive oxygen species (ROS) levels were markedly increased in KO hearts upon IPC, compared with IPC-WT hearts. Pre-treatment of KO hearts with a Rac-1 inhibitor NSC23766 (20 mg/kg, ip) reduced IPC-triggered ROS levels and restored IPC-elicited cardioprotection. Using antagomiRs, we showed that miR-451 was largely responsible for IPC-mediated cardioprotection. Loss of the miR-144/451 cluster limits IPC cardioprotection by up-regulating Rac-1-mediated oxidative stress signalling.Keywords
This publication has 41 references indexed in Scilit:
- Synergistic effects of the GATA-4-mediated miR-144/451 cluster in protection against simulated ischemia/reperfusion-induced cardiomyocyte deathJournal of Molecular and Cellular Cardiology, 2010
- The miR-144/451 locus is required for erythroid homeostasisThe Journal of Experimental Medicine, 2010
- Autophagy Induced by Ischemic Preconditioning is Essential for CardioprotectionJournal of Cardiovascular Translational Research, 2010
- Ischaemic preconditioning-regulated miR-21 protects heart against ischaemia/reperfusion injury via anti-apoptosis through its target PDCD4Cardiovascular Research, 2010
- MicroRNA control of signal transductionNature Reviews Molecular Cell Biology, 2010
- MicroRNA Expression Signature and the Role of MicroRNA-21 in the Early Phase of Acute Myocardial InfarctionJournal of Biological Chemistry, 2009
- MicroRNA expression in response to murine myocardial infarction: miR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologueCardiovascular Research, 2009
- A GATA-1-regulated microRNA locus essential for erythropoiesisProceedings of the National Academy of Sciences, 2008
- Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?Nature Reviews Genetics, 2008
- AMP‐activated protein kinase mediates preconditioning in cardiomyocytes by regulating activity and trafficking of sarcolemmal ATP‐sensitive K+ channelsJournal of Cellular Physiology, 2006