The Role Of Thiocyanate In Modulating Tissue Damage In Cardiovascular Disease

Abstract

Myeloperoxidase (MPO) is an enzyme released by activated neutrophils, monocytes, and some tissue macrophages as part of the inflammatory response at sites of inflammation. Thiocyanate anions (SCN-) are a major and preferred substrate for MPO, with oxidation giving rise to increased concentrations of hypothiocyanous acid (HOSCN) at the expense of hypochlorous acid (HOCl) which is generated from chloride ions. There is considerable evidence that these oxidants contribute to damage at sites of inflammation and contribute to the pathophysiology of cardiovascular diseases. HOSCN is much less reactive and more selective than HOCl, and the damage induced by HOSCN, which occurs primarily at Cys residues is generally reversible. Therefore, increased formation of HOSCN, at the expense of HOCl, driven by increasing thiocyanate levels, has been hypothesised to be protective against inflammation-induced damage. In this thesis, this hypothesis was investigated in the context of cardiovascular disease. Two animal models were utilised: a rat ischemia-reperfusion (IR) injury model and a mouse atherosclerosis model. Raising circulating SCN- levels was shown to protect rats from IR injury by reducing infarct size and protecting against pathological cardiac remodelling, as well as protecting mice against atherosclerosis at low concentrations by reducing plaque size and promoting a more stable plaque phenotype. Two pilot clinical studies were also implemented to investigate the role of SCN- and the MPO system in the context of asymptomatic vs. symptomatic cardiovascular disease (CVD), and also in sepsis. The MPO system was shown to be more active, and therefore detrimental, in the symptomatic CVD state as well as in sepsis subjects compared to controls. Overall, elevating circulating SCN- levels by dietary modulation has the potential to be protective in the context of CVD.