Abstract

Cardiomyocyte apoptosis in response to inflammation is a primary cause of myocardial ischemia-reperfusion injury (IRI). Nuclear factor erythroid 2 like 2 (Nrf2) reportedly plays an important role in myocardial IRI, but the underlying mechanism remains obscure. Expression data from the normal heart tissues of mice or heart tissues treated with reperfusion for 6 h after ischemia (IR6h) were acquired from the GEO database; changes in biological function and infiltrating immune cells were analyzed. The binding between the molecules was verified by chromatin immunoprecipitation sequencing. Based on confirmation that early myocardial ischemia-reperfusion (myocardial ischemia/reperfusion for 6 hours, IR6h) promoted myocardial apoptosis and inflammatory response, we found that Nrf2, cooperating with Programmed Cell Death 4, promoted transcription initiation of C-C Motif Chemokine Ligand 3 (Ccl3) in myocardial tissues of mice treated with IR6h. Moreover, Ccl3 contributed to the high signature score of C-C motif chemokine receptor 1 (Ccr1)-positive macrophages. The high signature score of Ccr1-positive macrophages leads to the release of pro-inflammatory factors interleukin 1 beta and interleukin 6. This study is the first to elucidate the damaging effect of Nrf2 via remodeling of the immune microenvironment in early myocardial ischemia-reperfusion, which provides us with new perspectives and treatment strategies for myocardial ischemia-reperfusion.

Highlights

  • Myocardial ischemia-reperfusion injury (MIRI) is defined as tissue damage that occurs when early and fast coronary flow returns to the heart after ischemia, which often exacerbates the damage caused by previous myocardial ischemia [1, 2]

  • Our previous studies focused on the role of PDCD4 and Nuclear factor erythroid 2 like 2 (Nrf2) in myocardial infarction (MI)/R

  • On the basis of confirming that early Myocardial ischemia-reperfusion (MI/R) (MI/R for 6 h, IR6h) promoted myocardial apoptosis and inflammatory response, we found that Nrf2, cooperating with Programmed cell death 4 (Pdcd4), promoted the transcription initiation of C Motif Chemokine Ligand 3 (Ccl3) in the myocardial tissues of mice treated with IR6h

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Summary

Introduction

Myocardial ischemia-reperfusion injury (MIRI) is defined as tissue damage that occurs when early and fast coronary flow returns to the heart after ischemia, which often exacerbates the damage caused by previous myocardial ischemia [1, 2]. A coordinated upregulation of inflammatory processes was observed in the ischemic area, whereas interstitial proteins, angiogenesis, and cardio-renal signaling processes were found to be increased at later reperfusion (days 4 and 7) [5]. As the master regulator of the cellular oxidative stress response, Nrf regulates many cytoprotective genes and plays a central role in defense mechanisms against oxidative and electrophilic insults [7]. Stabilized Nrf proteins form heterodimers with small Maf proteins in the nucleus and induce target gene expression for antioxidant reactions and detoxification by binding to antioxidant/electrophile response elements [9]. It plays an important role in the damage caused by oxidative stress. For the sake of uniformity, whether it’s human NRF2 or mouse Nrf, it’s written Nrf

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