Bilirubin Induced Cardioprotection: From Endogenous Protection to Therapeutic Potential

Abstract

Over the past 30 years, knowledge concerning the in vivo relevance of bilirubin has evolved from being an inert waste product of haem catabolism to a physiologically important antioxidant and biomarker of cardiovascular disease (CVD). Elevated serum bilirubin concentrations, as observed in human Gilbert’s syndrome (GS), are associated with reduced incidence of atherosclerosis, ischaemic heart disease (IHD), and a reduction in overall cardiovascular mortality. However, a comprehensive understanding of the mechanisms that might explain these associations remains to be delineated. Aside from its potent antioxidant capacity, bilirubin inhibits smooth muscle cell proliferation, intima-media thickening and influences vascular tone, all of which could represent additional mechanisms by which bilirubin could protect from CVD and associated mortality. This thesis addressed three aims; 1) to investigate whether endogenously elevated bilirubin affects cardiac structure and function in healthy rats; 2) to determine whether endogenously and exogenously elevated bilirubin impacts on cardiac stress resistance in aged and young rat hearts; and 3) to explore the effects of elevated endogenous bilirubin on expression of genes in left ventricular myocardium. If bilirubin was found to protect from myocardial ischaemia-reperfusion injury, the research within this thesis could underpin the development of therapies for myocardial infarction, for which there is currently no treatment.