An Interplay Between MRTF-A and the Histone Acetyltransferase TIP60 Mediates Hypoxia-Reoxygenation Induced iNOS Transcription in Macrophages.

Yuyu Yang,Yong Xu,Liming Yu,Guang Yang,Lin Lin,Mingming Fang,Li Liu

doi:10.3389/fcell.2020.00484

Abstract

Cardiac ischemia-reperfusion injury (IRI) represents a major pathophysiological event associated with permanent loss of heart function. Several inter-dependent processes contribute to cardiac IRI that include accumulation of reactive oxygen species (ROS), aberrant inflammatory response, and depletion of energy supply. Inducible nitric oxide synthase (iNOS) is a pro-inflammatory mediator and a major catalyst of ROS generation. In the present study we investigated the epigenetic mechanism whereby iNOS transcription is up-regulated in macrophages in the context of cardiac IRI. We report that germline deletion or systemic inhibition of myocardin-related transcription factor A (MRTF-A) in mice attenuated up-regulation of iNOS following cardiac IRI in the heart. In cultured macrophages, depletion or inhibition of MRTF-A suppressed iNOS induction by hypoxia-reoxygenation (HR). In contrast, MRTF-A over-expression potentiated activation of the iNOS promoter by HR. MRTF-A directly binds to the iNOS promoter in response to HR stimulation. MRTF-A binding to the iNOS promoter was synonymous with active histone modifications including trimethylated H3K4, acetylated H3K9, H3K27, and H4K16. Further analysis revealed that MRTF-A interacted with H4K16 acetyltransferase TIP60 to synergistically activate iNOS transcription. TIP60 depletion or inhibition achieved equivalent effects as MRTF-A depletion/inhibition in terms of iNOS repression. Of interest, TIP60 appeared to form a crosstalk with the H3K4 trimethyltransferase complex to promote iNOS trans-activation. In conclusion, we data suggest that the MRTF-A-TIP60 axis may play a critical role in iNOS transcription in macrophages and as such be considered as a potential target for the intervention of cardiac IRI.

Highlights

Cardiac ischemia, following such incidents as major surgeries or thrombosis, poses significant threat to the heart, and the survival of the organism
Since Inducible nitric oxide synthase (iNOS) activation has been implicated in the pathogenesis of cardiac ischemia-reperfusion injury (IRI), we asked whether myocardin-related transcription factor A (MRTF-A) might contribute to iNOS transcription in this process
8-week male wild type (WT), and MRTF-A knockout mice (KO) mice were subjected to cardiac IRI

Summary

Introduction

Cardiac ischemia, following such incidents as major surgeries (e.g., organ transplatation) or thrombosis, poses significant threat to the heart, and the survival of the organism. Attempts to resuscitate the ischemic heart can be met with restoration of the cardiac function but often, paradoxically, worsen the structural and functional loss of the myocardium and dampen the prognosis of the patients (Eltzschig and Eckle, 2011) This critical pathophysiological event, termed ischemia-reperfusion injury (IRI), is thought to be programmed by a series of independent yet inter-connected processes. Mitochondrial dysfunction during IRI promotes ROS generation but contributes to ATP depletion causing energy shortage (Tompkins et al, 2006) These processes are often paralleled by changes in gene expression patterns in the heart, characterized by up-regulation of enzymes involved in ROS production (e.g., NADPH oxidase), and pro-inflammatory mediators (Amberger et al, 2002)

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