Egr-1 functions as a master switch regulator of remote ischemic preconditioning-induced cardioprotection
Authors: A Dona
B S Rayner
L M Khachigian
M Billah
R Bhindi
U K Allahwala
A Ridiandries
Journal: Basic research in cardiology (2019)
Discipline: CLINICAL MEDICINE
Keywords: Egr-1; Interleukin-6; JAK–STAT; Myocardial Infarction; Remote preconditioning.
Affiliations: Department of Cardiology, Kolling Institute, Northern Sydney Local Health District, Level 12, Royal North Shore Hospital, Cnr Reserve Rd and Westbourne, St Leonards, NSW, 2065, Australia. ., Sydney Medical School Northern, University of Sydney, Sydney, NSW, 2006, Australia. ., School of Life Sciences, Independent University Bangladesh, Dhaka, Bangladesh. ., Department of Cardiology, Kolling Institute, Northern Sydney Local Health District, Level 12, Royal North Shore Hospital, Cnr Reserve Rd and Westbourne, St Leonards, NSW, 2065, Australia., Sydney Medical School Northern, University of Sydney, Sydney, NSW, 2006, Australia., Inflammation Group, Heart Research Institute, University of Sydney, Sydney, NSW, Australia., Vascular Biology and Translational Research, School of Medical Sciences, University of New South Wales, Sydney, Australia.

Abstract:  Despite improved treatment options myocardial infarction (MI) is still a leading cause of mortality and morbidity worldwide. Remote ischemic preconditioning (RIPC) is a mechanistic process that reduces myocardial infarction size and protects against ischemia reperfusion (I/R) injury. The zinc finger transcription factor early growth response-1 (Egr-1) is integral to the biological response to I/R, as its upregulation mediates the increased expression of inflammatory and prothrombotic processes. We aimed to determine the association and/or role of Egr-1 expression with the molecular mechanisms controlling the cardioprotective effects of RIPC. This study used H9C2 cells in vitro and a rat model of cardiac ischemia reperfusion (I/R) injury. We silenced Egr-1 with DNAzyme (ED5) in vitro and in vivo, before three cycles of RIPC consisting of alternating 5 min hypoxia and normoxia in cells or hind-limb ligation and release in the rat, followed by hypoxic challenge in vitro and I/R injury in vivo. Post-procedure, ED5 administration led to a significant increase in infarct size compared to controls (65.90 ± 2.38% vs. 41.00 ± 2.83%, p &lt; 0.0001) following administration prior to RIPC in vivo, concurrent with decreased plasma IL-6 levels (118.30 ± 4.30 pg/ml vs. 130.50 ± 1.29 pg/ml, p &lt; 0.05), downregulation of the cardioprotective JAK-STAT pathway, and elevated myocardial endothelial dysfunction. In vitro, ED5 administration abrogated IL-6 mRNA expression in H9C2 cells subjected to RIPC (0.95 ± 0.20 vs. 6.08 ± 1.40-fold relative to the control group, p &lt; 0.05), resulting in increase in apoptosis (4.76 ± 0.70% vs. 2.23 ± 0.34%, p &lt; 0.05) and loss of mitochondrial membrane potential (0.57 ± 0.11% vs. 1.0 ± 0.14%-fold relative to control, p &lt; 0.05) in recipient cells receiving preconditioned media from the DNAzyme treated donor cells. This study suggests that Egr-1 functions as a master regulator of remote preconditioning inducing a protective effect against myocardial I/R injury through IL-6-dependent JAK-STAT signaling. 

Retracted: No

PubPeer comments:
 Fig 5 shows same image of Normoxia cells as in Fig 3A of IJMS 21:1629 PMID 32121587 (with slight differences in brightness), but the cell viability is different, with 80% in BRC Fig 5, but 80% in IJMS Fig 3A. ![file] ,