Metformin Reverses the Effects of Angiotensin 2 in Human Mammary Arteries by Modulating the Expression of Nitric Oxide Synthases

Abstract Angiotensin 2 impairs vascular function by activation of reactive oxygen species (ROS) production and development of endothelial dysfunction. Metformin, the first-line therapeutic agent for type 2 diabetes mellitus, has vascular protective properties, beyond its glucose lowering effects. The aim of the present study was to in-vestigate the interaction between metformin and angiotensin 2 in human internal mammary arteries harvested from patients with coronary heart disease undergoing revascularization procedure, by evaluation of vascular function, reactive oxygen species (ROS) production and the gene expression of nitric oxide (NO) synthases (endothelial – eNOS, neuronal – nNOS and inducible – iNOS). To this aim, vascular samples were incubated with angiotensin 2 (Ang2, 12 h) with/without metformin (Metf, 10 μM) and used for ROS measurement (FOX assay), vascular reactivity in organ bath (contractility to phenylephrine, relaxation to acetylcholine, con-tractility to NG-nitro-L-arginine methyl ester/L-NAME) and RT-PCT studies. Acute incubation of the vascular rings with Ang2 im-paired vascular reactivity (increase contractility, decrease relax-ation), increased ROS production, supressed eNOS/nNOS and in-creased iNOS mRNA expression. Ex vivo incubation with metfor-min at a clinically relevant concentration reversed all these ef-fects. These data suggest that Metformin might be useful in allevi-ating endothelial dysfunction by improving the endothelial-de-pendent relaxation and mitigating oxidative stress in clinical set-ting associated with cardiovascular disease regardless the pres-ence of impaired glucose metabolism.