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
The current minireview aims to assess the implications of epicardial fat secretory function in the development of coronary artery disease. The epicardial adipose tissue (EAT) is a visceral fat depot that has been described as a cardiovascular risk factor. In addition to its mechanical protection role and physiological secretory function, it seems that various secretion products of the epicardial fat are responsible for metabolic disturbances at the level of the cardiac muscle when in association with pre-existing pathological conditions, such as metabolic syndrome. There is a pathological reduction in sarcomere shortening, abnormal cytosolic Ca2+ fluxes, reduced expression of sarcoplasmic endoplasmic reticulum ATPase 2a and decreased insulin-mediated Akt-Ser473-phosphorylation in association with abnormal levels of epicardial fat tissue. Activin A, angiopoietin-2, and CD14-positive monocytes selectively accumulate in the diseased myocardium, resulting in reduced cardiomyocyte contractile function. At the same time, it is believed that these alterations in secretory products directly decrease the myocyte function via molecular changes, thus contributing to the development of coronary disease when certain comorbidities are associated.
ABSTRACT
Mitochondrial dysfunction has emerged as a central pathomechanism in the setting of obesity and diabetes mellitus, linking these intertwined pathologies that share insulin resistance as a common denominator. High-resolution respirometry (HRR) is a state-of-the-art research method currently used to study mitochondrial respiration and its impairment in health and disease. Tissue samples, cells or isolated mitochondria are exposed to various substrate-uncoupler-inhibitor-titration protocols, which allows the measurement and calculation of several parameters of mitochondrial respiration. In this review, we discuss the alterations of mitochondrial bioenergetics in the main dysfunctional organs that contribute to the development of the obese and diabetic phenotypes in both animal models and human subjects. Herein we review data regarding the impairment of oxidative phosphorylation as integrated mitochondrial function assessed by means of HRR. We acknowledge the critical role of this method in determining the alterations in oxidative phosphorylation occurring in the early stages of metabolic pathologies. We conclude that there is a mutual two-way relationship between mitochondrial dysfunction and insulin insensitivity that characterizes these diseases.
