The Role of Extracellular DNA and Histones in Ischaemia-Reperfusion Injury of the Myocardium

Abstract

Despite an increase in the rates of survival in patients suffering myocardial infarction, as yet there is no therapy specifically targeting ischaemia and reperfusion injury of the myocardium. With a greater understanding of immune activation during infarction, more potential treatment targets are now being identified. The innate immune system is believed to play an important role in the myocardium after ischaemia-driven cardiomyocyte death. The release of intracellular contents including DNA into the extracellular space during necrosis and cell rupture is now believed to create a pro-inflammatory milieu which propagates the inflammatory process. DNA and DNA fragments have been shown to activate the innate immune system by acting as Danger-Associated Molecular Patterns (DAMPs), which act as ligands on toll-like receptors (TLRs). Stimulation of TLRs, in turn, can activate intracellular cell death pathways such as pyroptosis. Here, we review the role of DNA fragments during ischaemia and reperfusion, and assess their potential as a target in the quest to preserve cardiomyocyte viability following myocardial infarction.

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

“…Mitochondrial DNA (mtDNA) can be released in the extracellular space and in the circulatory system as a consequence of cell death. It can act as a DAMP and has the ability to activate the innate immune system (127)(128)(129). MtDNA is circular and carries unmethylated deoxycytidylate-phosphatedeoxyguanylate (CpG) regions similar to bacterial DNA and is therefore easily recognized as a DAMP (127,128).…”

Histone H4 aggravates inflammatory injury through TLR4 in chlorine gas-induced acute respiratory distress syndrome

“…In contrast, nucleosomes, composed of histones and DNA, appear to be less toxic [25,26]. Extracellular histones are DAMP molecules that can cause systemic inflammation involved in a wide range of inflammatory conditions, such as acute lung injury, liver injury, kidney injury, myocardial injury, cerebral stroke, coagulopathy, systemic lupus erythematosus, and even hair follicle death [27][28][29][30][31][32][33][34]. Extracellular histones can induce the release of chemokines, and activate the vascular endothelium, so as to facilitate leukocyte adhesion and transmigration [35,36].…”

Histone H4 aggravates inflammatory injury through TLR4 in chlorine gas-induced acute respiratory distress syndrome

“…In contrast, nucleosomes, composed of histones and DNA, appear to be less toxic [25,26]. Extracellular histones are DAMP molecules that can cause systemic in ammation involved in a wide range of in ammatory conditions, such as acute lung injury, liver injury, kidney injury, myocardial injury, cerebral stroke, coagulopathy, systemic lupus erythematosus, and even hair follicle death [27][28][29][30][31][32][33][34]. Extracellular histones can induce the release of chemokines, and activate the vascular endothelium, so as to facilitate leukocyte adhesion and transmigration [35,36].…”