Perturbation of cellular and vascular function by hyperglycaemia and hyperlipidaemia and their role in cardiovascular disease

Abstract

Hyperglycaemia and hyperlipidaemia are two major risk factors for the complications of diabetes mellitus. The research reported in this thesis investigates some of the molecular mechanisms linking diabetes with atherosclerosis, as well examining the anti-atherogenic potential of two anti-glycative and antioxidant compounds. The first two studies explored the effects of prolonged exposure to elevated glucose on the lysosomal system of monocytes/ macrophages: a critical aspect of cellular function. At concentrations of glucose comparable to that seen in diabetes there was impaired lysosmal activity discernible from early stages of cell maturation. The third study assessed the potential anti-atherogenic properties of carnosine in hyperglycaemic and hyperlipidaemic mice. Carnosine was shown to have an anti-hyperlipidaemic action and pro-fibrotic effects that may enhance plaque stability. The fourth study examined the anti-atherogenic, anti-lipidaemic and anti-inflammatory properties of nitroxide radical TEMPOL in obese and hyperlipidaemic mice. TEMPOL was shown to effectively block weight gain in mice; reduce the associated hyperlipidaemia and systemic inflammation; and reverse the switched adipokine profile of obesity. In follow up in vitro studies TEMPOL modulated high glucose-induced cytokine and adipokine release by human macrophages. These studies have identified a mechanism by which hyperglycaemia promotes atherosclerosis as well as identifying potential therapeutic agents.