Involvement of inflammatory oxidants in cardiac ischaemia/reperfusion injury

Abstract

Oxidative stress is a major feature of cardiac ischaemia/reperfusion (I/R) injury, with strong evidence implicating infiltrating leukocytes, in particular neutrophils, as a major source of oxidants in the infarcted myocardium. Activated leukocytes release the peroxidase enzyme, myeloperoxidase (MPO), which can produce the oxidants hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). Chapter 3 examines the differential cellular effect of (patho)-physiological levels of HOCl and HOCN in cardiomyocytes. Both HOCl and HOSCN induced cellular damage characteristic of cardiac I/R injury and highlighted two very different cellular responses in cardiomyocytes. Chapter 4 explored the therapeutic effect of selenium supplements, specifically, the dietary supplement selenomethionine (SeMet) as a form of antioxidant therapy in the in vitro cardiomyocyte model exposed to HOCl and HOSCN or hypoxia/re-oxygenation (H/R). SeMet prevented a range of cellular damage mediated by HOCl, with the protection mainly attributed to the direct scavenging ability of SeMet. In contrast, SeMet was not able to protect against the HOSCN or H/R injury induced damage. Studies were extended in Chapter 5 to examine SeMet’s ability to modulate the cellular damage observed in an experimental in vivo model of cardiac I/R injury. SeMet (2 mg kg-1) for 8 weeks resulted in the elevation of tissue selenium levels and reduced apoptosis mediated by acute I/R injury, but not the accompanying cardiac dysfunction, adverse remodelling or impaired cardiac function during late stage I/R injury. Overall, this Thesis contributed to knowledge regarding the role of HOCl and HOSCN in cardiac I/R injury, with the results suggesting that both oxidants may contribute to oxidative stress and the associated downstream cellular damage. Furthermore, this work shows that SeMet could be beneficial as secondary treatment for cardiac I/R injury and be used in conjunction with current treatment methods.