The role of RIPK3‐regulated cell death pathways and necroptosis in the pathogenesis of cardiac ischaemia‐reperfusion injury

Abstract

Despite advancements in management of acute myocardial infarction, this disease remains one of the leading causes of death. Timely reestablishment of epicardial coronary blood flow is the cornerstone of therapy; however, substantial amount of damage can occur as a consequence of cardiac ischaemia/reperfusion (I/R) injury. It has been previously proposed that the pathway leading to major cell death, apoptosis, is responsible for cardiac I/R injury. Nevertheless, there is compelling evidence to suggest that necroptosis, a programmed necrosis, contributes remarkably to both myocardial injury and microcirculatory dysfunction following cardiac I/R injury. Receptor‐interacting protein kinase 1 (RIPK1), RIPK3, and mixed‐lineage kinase domain‐like pseudokinase (MLKL) are shown as the major mediators of necroptosis. In addition to the traditional perception that RIPK1/RIPK3/MLKL‐dependent plasma membrane rupture is fundamental to this process, several RIPK3‐related pathways such as endoplasmic reticulum stress and mitochondrial fragmentation have also been implicated in cardiac I/R injury. In this review, reports from both in vitro and in vivo studies regarding the roles of necroptosis and RIPK3‐regulated necrosis in cardiac I/R injury have been collectively summarized and discussed. Furthermore, reports on potential interventions targeting these processes to attenuate cardiac I/R insults to the heart have been presented in this review. Future investigations adding to the knowledge obtained from these previous studies are needed in the pursuit of discovering the most effective pharmacological agent to improve cardiac I/R outcomes.

Selenium ameliorates aflatoxin B1‐induced uterine injury in female mice and necrosis of human endometrial microvascular endothelial cells

“…Contrary to apoptosis, necrosis is a death program that does not depend on caspase. Necrosis mainly depends on RIPK1, RIPK3, and MLKL signaling (Ying, Benjanuwattra, Chattipakorn, & Chattipakorn, 2020). Our data revealed that AFB1 exposure promoted necrosis activation of HEMECs, which was distinctly ameliorated by Se treatment.…”

Targeting necroptosis as therapeutic potential in chronic myocardial infarction

“…The loss of functional cardiomyocytes and increased fibrosis are responsible for cardiac contractile dysfunction and failure [ 24 – 27 ]. Of note, necroptosis is inherently immunogenic since it leads to the disruption of plasma membrane, thereby causing the release of pro-inflammatory biomolecules (collectively called damage-associated molecular patterns, DAMPs) [ 13 , 57 , 58 ]. In addition, ongoing progression of chronic MI has been associated with diverse types of cell death mechanisms [ 13 ].…”

“…Both electrical and mechanical defects evolve in the inflamed myocardium as a consequence of progressive cardiomyocyte loss and abnormal extracellular matrix deposition [ 66 , 67 ]. Necroptosis is known as one of the regulated forms of necrosis that initiate a robust inflammatory response by a release of DAMPs from the disruption of the plasma membrane [ 58 ]. The consequence following RIPK3-mediated necroptosis is the aggravation of inflammatory processes in various organs, including the heart, intestine and skin [ 58 , 68 – 70 ].…”

“…Necroptosis is known as one of the regulated forms of necrosis that initiate a robust inflammatory response by a release of DAMPs from the disruption of the plasma membrane [ 58 ]. The consequence following RIPK3-mediated necroptosis is the aggravation of inflammatory processes in various organs, including the heart, intestine and skin [ 58 , 68 – 70 ]. In the heart tissue of MI mice, the boundary between the infarcted area and the non-infarcted area had significantly increased inflammatory cells infiltration [ 25 ].…”

“…The activation of caspase-8 would result in cardiomyocyte loss through the apoptosis pathway, whereas the inhibition of caspase-8 in complex IIb induced the phosphorylation of RIPK1 and RIPK3 and formed pro-necrotic complexes or necrosomes, leading to necroptosis [ 13 , 50 , 79 ]. Accordingly, the regulation of caspase-8 activities is essential for determining the fate of cell death between apoptosis and necroptosis [ 13 , 58 ]. However, the precise mechanisms or mediators which ultimately determine the dominant cell death pathway remains unclear.…”