Abstract
Oxidative stress is a major hallmark of cardiac ischemia/reperfusion (I/R) injury. This partly arises from the presence of activated phagocytes releasing myeloperoxidase (MPO) and its production of hypochlorous acid (HOCl). The dietary supplement selenomethionine (SeMet) has been shown to bolster endogenous antioxidant processes as well as readily react with MPO-derived oxidants. The aim of this study was to assess whether supplementation with SeMet could modulate the extent of cellular damage observed in an in vitro cardiac myocyte model exposed to (patho)-physiological levels of HOCl and an in vivo rat model of cardiac I/R injury. Exposure of the H9c2 cardiac myoblast cell line to HOCl resulted in a dose-dependent increase in necrotic cell death, which could be prevented by SeMet supplementation and was attributed to SeMet preventing the HOCl-induced loss of mitochondrial inner trans-membrane potential, and the associated cytosolic calcium accumulation. This protection was credited primarily to the direct oxidant scavenging ability of SeMet, with a minor contribution arising from the ability of SeMet to bolster cardiac myoblast glutathione peroxidase (GPx) activity. In vivo, a significant increase in selenium levels in the plasma and heart tissue were seen in male Wistar rats fed a diet supplemented with 2 mg kg−1 SeMet compared to controls. However, SeMet-supplementation demonstrated only limited improvement in heart function and did not result in better heart remodelling following I/R injury. These data indicate that SeMet supplementation is of potential benefit within pathological settings where excessive HOCl is known to be generated but has limited efficacy as a therapeutic agent for the treatment of heart attack.
Highlights
Strong evidence has shown a role of infiltrating leukocytes in mediating host tissue damage during and following cardiac ischemia/reperfusion (I/R) injury [1,2,3,4], which may in part be due to their role in contributing to oxidative stress within this environment [5]
We have previously demonstrated that the concentration of hypochlorous acid (HOCl) required to elicit detrimental changes to H9c2 cells was between 40 μM and 50 μM [58]
The ability of SeMet to protect against cellular damage induced by these concentrations of HOCl in H9c2 cells was first assessed by examining mitochondrial function with flow cytometry and JC-1 staining
Summary
Strong evidence has shown a role of infiltrating leukocytes in mediating host tissue damage during and following cardiac ischemia/reperfusion (I/R) injury [1,2,3,4], which may in part be due to their role in contributing to oxidative stress within this environment [5]. Given that oxidative stress has been established as a prominent feature of cardiovascular disease (CVD) and owing to their demonstrated ability to act as potent scavengers of radical species [10,11,12,13], antioxidant administration remains a potentially beneficial therapy within this setting Despite this knowledge and the fact that prior benefits have been demonstrated within in vitro settings, through the use of a variety of vitamins and polyphenolic compounds [11], the vast majority of human clinical trials involving antioxidant supplementation have demonstrated a lack of benefit of these agents in the prevention of CVD [14]. This mainly stems from the challenge of achieving a high enough concentration of the antioxidant therapeutic in the correct location or cellular compartment to compete with the more abundant cellular targets
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