TXNIP/Redd1 signalling and excessive autophagy: a novel mechanism of myocardial ischaemia/reperfusion injury in mice

Abstract

Aims Either insufficient or excessive autophagy causes cellular death and contributes to myocardial ischaemia/reperfusion (I/R) injury. However, mechanisms controlling the ‘right-level’ of autophagy in the heart remains unidentified. Thioredoxin-interacting protein (TXNIP) is a pro-oxidative molecule knowing to contribute to I/R injury. However, whether and how TXNIP may further inhibit suppressed autophagy or promote excessive cardiac autophagy in I/R heart has not been previously investigated. Methods and results Wild type or gene-manipulated adult male mice were subjected to myocardial I/R. TXNIP was increased in myocardium during I/R. Cardiac-specific TXNIP overexpression increased cardiomyocytes apoptosis and cardiac dysfunction, whereas cardiac-specific TXNIP knock-out significantly mitigated I/R-induced apoptosis and improved cardiac function. Importantly, TXNIP overexpression significantly promoted cardiac autophagy and TXNIP knock-out significantly inhibited cardiac autophagy. In vitro studies demonstrated that TXNIP increased autophagosome formation but inhibited autophagosome clearance during myocardial reperfusion. Atg5 siRNA significantly decreased hypoxia/reoxygenation induced apoptosis in cardiomyocytes with TXNIP overexpression. Mechanistically, TXNIP suppressed autophagosome clearance via increasing reactive oxygen species (ROS) level. However, TXNIP-increased autophagosome formation was not mediated by ROS as a ROS scavenger failed to block increased autophagosome formation in TXNIP overexpression heart. Finally, TXNIP directly interacted and stabilized Redd1 (an autophagy regulator), resulting in mTOR inhibition and autophagy activation. Redd1 knock-down significantly reduced autophagy formation and ameliorated I/R injury in TXNIP overexpression hearts. Conclusions Our results demonstrated that increased TXNIP-Redd1 expression is a novel signalling pathway that contributes to I/R injury by exaggerating excessive autophagy during reperfusion. These observations advance our understanding of the mechanisms of myocardial I/R injury.

Ubc9 Attenuates Myocardial Ischemic Injury Through Accelerating Autophagic Flux

“…Indeed, in recent years, there have been increasing numbers of studies unveiling new information on autophagy. Emerging evidence has revealed that autophagy may also promote cell death through excessive autophagosomes formation, which can be obtained from recent papers (Wang et al, 2015;Gao et al, 2018;Gao et al, 2019). These groups demonstrate that inhibition of redundant autophagosomes effectively protects cardiomyocytes from ischemic injury.…”

“…The apoptotic cardiomyocytes were stained with TUNEL dye (Gao et al, 2019). Procedures are described in Supplementary data.…”

MicroRNA-103 Protects Coronary Artery Endothelial Cells against H2O2-Induced Oxidative Stress via BNIP3-Mediated End-Stage Autophagy and Antipyroptosis Pathways

“…Although the role of autophagy in oxidative stress has been widely examined in recent years, few studies have specifically addressed the role of end-stage autophagy, and those that have, yielded controversial results [7,8]. For instance, ROS were found to inhibit the clearance of autophagic lysosomes at the end of the ischemia-reperfusion period, thus promoting the occurrence of cell apoptosis and aggravating cell damage [9], while other studies have suggested that promoting autophagy can reduce the inflammatory response caused by mitochondrial damage [10]. Recently, a new type of programmed cell death, pyroptosis has been described, which consists of focal cell death primarily occurring through recognition of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), which activates the immune cell receptor and promotes the expression of NOD-like receptor family, pyrin domain containing 3 (NLRP3), caspase 1, and interleukin-(IL-) 1β, as well as other inflammatory factors [11,12].…”

Protective effects of dexmedetomidine on hypoxia/reoxygenation injury in cardiomyocytes by regulating the CHOP signaling pathway

“…During reperfusion, a large amount of inflammatory factors is produced to promote tissue infiltration of inflammatory cells, thus affecting cell structures and functions ( 11 ). Hypoxia/reoxygenation (H/R) in cells is a major characteristic of I/R, and is frequently used to simulate the activity of I/R ( 12 , 13 ). Low cell viability, high apoptosis and inflammatory responses occur after cell injury induced by H/R ( 14 ).…”