Brite Adipocyte FGF21 Attenuates Cardiac Ischemia/Reperfusion Injury in Rat Hearts by Modulating NRF2.

Hanbyeol Moon,Sang Woo Kim,Jung-Won Choi,Il-Kwon Kim,Seahyoung Lee,Ki-Chul Hwang,Gyoonhee Han,Byeong-Wook Song,Soyeon Lim

doi:10.3390/cells11030567

Hanbyeol Moon, Sang Woo Kim + Show 7 more

Open Access

https://doi.org/10.3390/cells11030567

Copy DOI

Abstract

Although the optimal therapy for myocardial infarction includes reperfusion to restore blood flow to the ischemic area, myocardial injury after ischemia/reperfusion usually leads to an inflammatory response, oxidative stress, and cardiomyocyte apoptosis. In this study, rat adipose-derived stem cells were differentiated into low-thermogenic beige adipocytes (LBACs) and high-thermogenic beige adipocytes (HBACs) to study the different cardioprotective effects of heterogeneous expression of brown adipocytes. We found that antioxidant and antiapoptotic factors in H9c2 cardiomyocytes were upregulated by high levels of secreted FGF21 in HBAC conditioned medium (HBAC-CM), whereas FGF21 in HBAC-CM did not affect antioxidative or antiapoptotic cell death in H9c2 cardiomyocytes with Nrf2 knockdown. These results show that NRF2 mediates antioxidative and antiapoptotic effects through the HBAC-secreted factor FGF21. Consistent with this finding, the expression of antioxidant and antiapoptotic genes was upregulated by highly secreted FGF21 after HBAC-CM treatment compared to LBAC-CM treatment in H9c2 cardiomyocytes via NRF2 activation. Furthermore, HBAC-CM significantly attenuated ischemic rat heart tissue injury via NRF2 activation. Based on these findings, we propose that HBAC-CM exerts beneficial effects in rat cardiac ischemia/reperfusion injury by modulating NRF2 and has potential as a promising therapeutic agent for myocardial infarction.

Highlights

Introduction published maps and institutional affilIschemic heart disease including acute myocardial infarction is the leading cause of morbidity and mortality, and appropriate restoration of blood flow to the ischemic myocardium is indispensable [1,2]
We investigated whether white adipocytes differentiated from human adipose-derived stromal cells (ASCs) could increase brown adipogenesis by expressing uncoupling protein 1 (UCP-1) and PR/SET domain 16 (PRDM16) due to small molecule treatments in a previous study [27]
We demonstrated that the activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2) was increased by Fibroblast growth factor 21 (FGF21), a factor secreted from beige adipocytes (BACs), which leads to increases in antioxidative effects and subsequently reduces apoptosis, alleviating IR injury

Summary

Introduction

Ischemic heart disease including acute myocardial infarction is the leading cause of morbidity and mortality, and appropriate restoration of blood flow (reperfusion) to the ischemic myocardium is indispensable [1,2]. This reperfusion may cause further myocardial ischemia/reperfusion (IR) injury that can induce heart failure and endothelial and microvascular dysfunction and have more serious adverse effects on other myocardial tissues. Oxidative stress is one of the most critical mechanisms of the complicated networks associated with cardiovascular diseases such as myocardial IR injury [3,4].

Objectives

Methods

Results

Conclusion