Understanding how released histones exert their toxic effects on the heart

Mechanisms of cardiomyocyte dysfunction induced by extracellular histones 

Histones are a family of proteins which provide structural support to DNA. In healthy cells, histones (along with DNA) are found in the nucleus (the command centre of the cell). When cells are damaged and die e.g. due to a lack of oxygen, infection, or injury, histones are released into nearby tissue and the bloodstream. Released histones are toxic to cells, this means circulating histones can then cause damage to other tissues and organs (secondary damage). Circulating histones are known to cause secondary damage to the heart following sepsis (a severe reaction to infection) and physical injury. Released histones have also been found in damaged heart muscle following a heart attack. In this project, Professor Derek Steele and colleagues at the University of Leeds will investigate precisely how histones exert their toxic effects on the heart. The researchers will monitor the behaviour of heart cells and hearts from rats exposed to histones, using advanced microscopy techniques and by recording their electrical activity. They also plan to investigate whether existing drugs that decrease the positive charge of histones (histone deacetylase inhibitors) reduce their toxic effects. This research could lead to new treatments being adopted to protect the heart from secondary damage caused by histones.