AGEing heart valves: a bittersweet stiffening process?

The robust link between diabetes and the development of cardiovascular diseases (CVD)1 ,2 has sparked considerable efforts to unravel the underlying mechanisms driving this process. Although diabetes-related CVD onset is complex and multifactorial in nature, there is an increased focus on hyperglycaemia as a significant contributor. For example, the widely touted ‘unifying hypothesis of diabetes’ emphasises the detrimental effects of hyperglycaemia-mediated oxidative stress.3 In this instance, the proposal is put forward that excess mitochondrial superoxide triggers genotoxic effects in the nucleus thereby enhancing poly(ADP-ribosyl)ation to counteract DNA damage. It is further postulated that poly(ADP-ribosyl)ation attenuates the activity of the glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase, causing the upstream accumulation of glycolytic metabolites.4 The latter are subsequently shunted into various non-oxidative glucose pathways (NOGPs), that is, the polyol pathway, formation of advanced glycation end products (AGEs), the hexosamine biosynthetic pathway and the activation of protein kinase C.5 Our laboratory recently suggested that a vicious metabolic cycle is established whereby hyperglycaemia-induced NOGP stimulation further fuels its own activation by generating even more oxidative stress and exacerbating damaging effects in the heart.5 The AGE pathway emerges as a key therapeutic target for diabetes-related CVD onset. For example, serum AGE levels are significantly higher in patients with diabetes having coronary heart disease compared with those without.6 The effects of AGEs are also more widely spread as there is enhanced formation with chronic inflammation, ageing and renal failure.7 ,8 AGE levels can also increase in response to poor dietary choices9 while reactive glycation products are present in aqueous extracts of tobacco and in tobacco smoke in a form that can rapidly react with proteins to form AGEs.10 Non-enzymatic protein glycation occurs through a series …