ABSTRACT
Metformin, the first-line drug in type 2 diabetes mellitus, elicits cardiovascular protection also in obese patients via pleiotropic effects, among which the anti-oxidant is one of the most investigated. The aim of the present study was to assess whether metformin can acutely mitigate oxidative stress in atrial tissue harvested from overweight non-diabetic patients. Right atrial appendage samples were harvested during open-heart surgery and used for the evaluation of reactive oxygen species (ROS) production by means of confocal microscopy (superoxide anion) and spectrophotometry (hydrogen peroxide). Experiments were performed after acute incubation with metformin (10 µM) in the presence vs. absence of angiotensin II (AII, 100 nM), lipopolysaccharide (LPS, 1 µg/mL), and high glucose (Gluc, 400 mg/dL). Stimulation with AII, LPS, and high Gluc increased ROS production. The magnitude of oxidative stress correlated with several echocardiographic parameters. Metformin applied in the lowest therapeutic concentration (10 µM) was able to decrease ROS generation in stimulated but also non-stimulated atrial samples. In conclusion, in a pilot group of overweight non-diabetic cardiac patients, acute incubation with metformin at a clinically relevant dose alleviated oxidative stress both in basal conditions and conditions that mimicked the activation of the renin-angiotensin-aldosterone system, acute inflammation, and uncontrolled hyperglycemia.
ABSTRACT
Chronic inflammation is the hallmark of cardiovascular pathologies with a major role in both disease progression and occurrence of long-term complications. The massive release of ATP during the inflammatory process activates various purinergic receptors, including P2Y11. This receptor is less studied but ubiquitously expressed in all cells relevant for cardiovascular pathology: cardiomyocytes, fibroblasts, endothelial and immune cells. While several studies suggested a potential pro-inflammatory role for P2Y11 receptors, recent literature data are supportive of an anti-inflammatory profile characterized by the immunosuppression of dendritic cells, inhibition of fibroblast proliferation and of cytokines and ATP secretion. Moreover, modulation of its activity appears to mediate the positive inotropic effect of ATP and mitigate endothelial dysfunction, thus rendering this receptor a promising therapeutic target in the cardiovascular disease armamentarium. The aim of the present review is to summarize the current available knowledge on P2Y11-related purinergic signaling in the setting of inflammation and cardio-metabolic diseases.