Extracellular histones are a target in myocardial ischaemia–reperfusion injury

Abstract

Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). Histones have been described as important Danger Associated Molecular Proteins (DAMPs) in sepsis. Aims The objective of this study was to establish whether extracellular histone release contributes to myocardial infarction. Methods and results Isolated, perfused rat hearts were subject to I/R. Nucleosomes and histone H4 release was detected early during reperfusion. Sodium-β-O-Methyl cellobioside sulfate (mCBS), a newly developed histone-neutralising compound, significantly reduced infarct size whilst also reducing the detectable levels of histones. Histones were directly toxic to primary adult rat cardiomyocytes in vitro. This was prevented by mCBS, or HIPe, a recently described, histone-H4 neutralizing peptide, but not by an inhibitor of TLR4, a receptor previously reported to be involved in DAMP-mediated cytotoxicity. Furthermore, TLR4-reporter HEK293 cells revealed that cytotoxicity of histone H4 was independent of TLR4 and NF-κB. In an in vivo rat model of I/R, HIPe significantly reduced infarct size. Conclusion Histones released from the myocardium are cytotoxic to cardiomyocytes, via a TLR4-independent mechanism. The targeting of extracellular histones provides a novel opportunity to limit cardiomyocyte death during I/R injury of the myocardium. Translational perspective Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). New approaches are needed to prevent cardiomyocyte injury and limit final infarct size. We show that histones released from damaged cells, and histone-H4 in particular, causes rapid cardiomyocyte death during I/R. mCBS, a compounds targeting histones non-specifically, was cardioprotective in ex vivo rat hearts, while HIPe, a targeting histone H4 specifically, was cardioprotective in an in vivo rat model. HIPe may have potential as a therapeutic agent in the setting of acute myocardial infarction.

Do Circulating Histones Represent the Missing Link among COVID-19 Infection and Multiorgan Injuries, Microvascular Coagulopathy and Systemic Hyperinflammation?

“…This outstanding and elegant research sheds light on the significant correlation between plasma histone levels and severity of COVID-19 infection, highly associated with severe coagulopathy, inflammation, and cardiac injury. In particular, the plasma levels of cardiac troponin were found to correlate with histone levels and were found to be significantly higher in COVID-19 patients who died compared to those who survived (median circulating histone levels in non-survivors vs. survivors: 29.6 μg/mL vs. 8.6 μg/mL, p = 0.002) [ 29 ], thus confirming literature data on both cytotoxic effects of extracellular histones on cardiomyocytes [ 25 ], and non-necrotic cardiac troponin release in COVID-19 patients [ 30 ].…”

“…A plethora of recent studies underlining the roles and functions of extracellular histones as biomarkers for predicting outcomes of several human diseases have also been published [ 22 , 23 ]. Recent evidence especially demonstrates that the levels of NETs and histones may predict the cardiovascular risk [ 7 ], wherein circulating histones may function as signaling scaffold at the culprit site of myocardial infarction and stroke [ 24 , 25 , 26 , 27 , 28 ], also in COVID-19 patients with cardiac manifestations.…”

“…All these observations suggest that injuries to the heart tissue caused directly by SARS-CoV-2 and/or indirectly by the release of histones SARS-CoV-2-related can be underlying causes of heart diseases (e.g., myocarditis and myocardial ischemia) in COVID-19 [ 25 , 29 , 32 , 33 ].…”

Extracellular Nucleosomes Accelerate Microglial Inflammation via C-Type Lectin Receptor 2D and Toll-Like Receptor 9 in mPFC of Mice With Chronic Stress

“…Extracellular histones, damaged nucleosomes, and cell-free DNA are well-known nuclear DAMPs that efficiently induce inflammation, cytotoxicity, and tissue damage. More recently, extracellular histone-induced tissue damage and death have become hot issues of medical concern in sepsis, trauma, ischemia/reperfusion (I/R) injury, and autoimmune diseases (51)(52)(53)(54)(55). There are three distinct extracellular forms of histone: free histones, DNA-bound histones (nucleosomes), and neutrophil extracellular traps (NET; webs of extracellular DNA decorated with histones, myeloperoxidase, and elastase).…”

Effects of Trauma-Related Shock on Myocardial Function in the Early Period Using Transthoracic Echocardiography

“…Multiple DAMPs (e.g., heat shock proteins, high mobility group box-1 [HMGB-1], adenosine triphosphate, nuclear and mitochondrial DNA [mtDNA], and RNA) play a role in myocardial ischemia-reperfusion injury. DAMP activation may eventually lead to reperfusion-induced cardiac damage [23][24][25][26]. Weber et al [27] suggest that resultant structural alterations in the heart might be consequences of the complementary events: DAMP activation, the release of extracellular histones, and systemic TNF elevation.…”