Nitric oxide regulation of cardiac function, metabolism and inflammation in diabetes.
Our group is interested in the study of diabetes mellitus as it is a major cause of death and disability and a large economic burden on health care systems across the world. Globally, 1 in 12 all-cause deaths in adults have been attributed to diabetes and its complications. Epidemiological data suggest that diabetes may in itself give rise to a specific cardiomyopathy, characterised by progressively impaired left ventricular (LV) diastolic function and, in humans, a predominant phenotype of heart failure with preserved ejection fraction (HFpEF). Despite current glucose lowering therapies, people with diabetes are still at a higher risk of developing heart disease.
Excessive production of reactive oxygen species, metabolic disturbances (eg alterations in substrate supply or utilisation), remodelling of the extracellular matrix and mitochondrial dysfunction have been advocated as main determinants of both vascular and myocardial dysfunction in diabetes. However, a unifying mechanism upstream of the observed LV functional changes is still missing.
We have investigated the molecular signature of diabetes in heart cells/muscle of patients and animal models and discovered that increases in the myocardial level of tetrahydrobiopterin (BH4) can prevent cardiac dysfunction. BH4 is a key cofactor of nitric oxide synthase (NOS), and is responsible for maintaining the enzyme's function in the presence of oxidative stress. These findings open the possibility that BH4 supplementation may provide a novel therapeutic tool in the management of patients with diabetes and HFpEF.
The aim of our research is to understand how diabetes alters the cardiovascular system in an early stage and elucidate the mechanisms by which nitric oxide may protect the heart in the presence of diabetes.
Drew Duglan – DPhil Student
Simona Mafrici – DPhil Student