Elements of the molecular pathways responsible for the action of metformin in protecting against cardiovascular disease in diabetes have been revealed by a new study conducted by researchers from King Abdulaziz University in Saudi Arabia and Newcastle University in the UK. Funded by KACST, the team managed to reveal the mechanisms of action of the drug, and identify potential therapeutic targets to reduce morbidity and mortality in diabetes.
People with diabetes are more likely to develop cardiovascular disease (CVD), and for them, the outcomes of its management are worse than in healthy people. Metformin protects against cardiovascular disease in people with diabetes, but the mechanisms that underlie its protective effect remain unclear. Jolanta Weaver from the University of Newcastle, UK, and colleagues had previously shown that metformin promotes the growth of blood vessels, a process called angiogenesis. In a new study, the team has examined the direct molecular effects of metformin on the endothelial cells that line the inside of blood vessel walls.
The researchers used human umbilical vein endothelial cells in culture and treated them with metformin in conditions that mimicked diabetes: cells were exposed to high blood sugar levels (hyperglycaemia) and/or starved of oxygen (hypoxia). The extent of hyperglycaemia and hypoxia and the dose of metformin were all kept within physiological ranges to ensure the clinical relevance of the findings.
The cellular effects of metformin in the diabetes-mimicking conditions were then compared with the effects in normal physiological conditions. These effects were assessed by measuring activity in the vascular endothelial growth factor (VEGF) signalling pathway, which was shown to be involved in angiogenesis in the group’s previous study and is known to be disrupted in diabetes.
Under the conditions that mimicked diabetes, metformin was found to have two effects on endothelial cells: it promoted endothelial cell migration and inhibited cell death. Both effects were mediated by increased expression of the VEGF receptors VEGFR1 and VEGFR2, both of which activate signalling cascades that protect endothelial cells. Cell migration was activated by increasing cellular response to matrix metalloproteinase 16 (MMP16) and Rho kinase 1 (ROCK1), and inhibition of cell death was mediated by increased expression of phospho-extracellular signal-related kinase (ERK) 1 or 2 and of fatty acid binding protein 4 (FABP4).
The findings indicate that restoration of the VEGF signalling pathway could be effective for reducing cardiovascular risk in people with diabetes. Identifying specific elements in the pathway that are involved in this process could pinpoint novel therapeutic targets.
Bakhashab, S., Ahmed, F., Schulten, H.-J., Ahmed, F., Glanville, M. et al. Proangiogenic effect of metformin in endothelial cells is via upregulation of VEGFR1/2 and their signaling under hyerglycemia–hypoxia. International Journal of Molecular Sciences 2018, 293 (2018). | article