Molecular mechanisms of cardiac pathology in diabetes - Experimental insights.

Diabetic cardiomyopathy is a distinct pathology independent of co-morbidities such as coronary artery disease and hypertension. Diminished glucose uptake due to impaired insulin signaling and decreased expression of glucose transporters is associated with a shift towards increased reliance on fatty acid oxidation and reduced cardiac efficiency in diabetic hearts. The cardiac metabolic profile in diabetes is influenced by disturbances in circulating glucose, insulin and fatty acids, and alterations in cardiomyocyte signaling. In this review, we focus on recent preclinical advances in understanding the molecular mechanisms of diabetic cardiomyopathy. Genetic manipulation of cardiomyocyte insulin signaling intermediates has demonstrated that partial cardiac functional rescue can be achieved by upregulation of the insulin signaling pathway in diabetic hearts. Inconsistent findings have been reported relating to the role of cardiac AMPK and ß-adrenergic signaling in diabetes, and systemic administration of agents targeting these pathways appear to elicit some cardiac benefit, but whether these effects are related to direct cardiac actions is uncertain. Overload of cardiomyocyte fuel storage is evident in the diabetic heart, with accumulation of glycogen and lipid droplets. Cardiac metabolic dysregulation in diabetes has been linked with oxidative stress and autophagy disturbance, which may lead to cell death induction, fibrotic 'backfill' and cardiac dysfunction. This review examines the weight of evidence relating to the molecular mechanisms of diabetic cardiomyopathy, with a particular focus on metabolic and signaling pathways. Areas of uncertainty in the field are highlighted and important knowledge gaps for further investigation are identified. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.

DNAzymes and cardiovascular disease.

Gene silencing techniques are gaining increasing popularity in the literature, both as a tool for unravelling gene function and to potentially deliver therapeutic benefit, especially in the context of cardiovascular disease. Gene-specific catalytic DNA molecules, or DNAzymes, have shown promise in ameliorating the effects of myocardial ischaemia reperfusion injury and in-stent restenosis in various animal models, demonstrating that these agents may be useful in a clinical setting. A review of the recent advances in the use of DNAzymes in treating cardiovascular disease is therefore essential given the increasing clinical burden of cardiovascular disease worldwide. We have thus sought to firstly provide background into the construct and mechanism of action of DNAzymes, with a discussion of recent improvements in design. Secondly, we have examined the effects of DNAzyme-mediated gene inhibition in in vitro studies of both endothelial and smooth muscle migration and proliferation, as well as in vivo models of acute myocardial infraction and neointima formation. Lastly we compare DNAzymes with other gene silencing tools and discuss issues involved in successfully delivering these drugs in a clinical setting.

sICAM-1 measurements are independent of processing method and sampling site in patients with coronary artery disease.

sICAM-1 measurements are here shown to be independent of processing method (serum, platelet rich and platelet poor plasma) and sampling size (venous or arterial blood) in patients with coronary disease.