RESUMEN
Cardiovascular diseases represent the major cause of morbidity mainly due to chronic heart failure. Epicardial (EAT) and perivascular adipose tissues (PVAT) are considered major contributors to the pathogenesis of cardiometabolic pathologies. Monoamine oxidases (MAOs) are mitochondrial enzymes recognized as sources of reactive oxygen species (ROS) in cardiometabolic pathologies. Methylene blue (MB) is one of the oldest protective agents, yet no data are available about its effects on adipose tissue. The present pilot study was aimed at assessing the effects of MB: (i) on MAO expression and (ii) oxidative stress in EAT and PVAT harvested from patients with heart failure subjected to cardiac surgery (n = 25). Adipose tissue samples were incubated with MB (0.1 µM/24 h) and used for the assessment of MAO gene and protein expression (qPCS and immune fluorescence) and ROS production (confocal microscopy and spectrophotometry). The human cardiovascular adipose tissues contain both MAO isoforms, predominantly MAO-A. Incubation with MB reduced MAOs expression and oxidative stress; co-incubation with serotonin, the MAO-A substrate, further augmented ROS generation, an effect partially reversed by MB. In conclusion, MAO-A is the major isoform expressed in EAT and PVAT and contribute to local oxidative stress; both effects can be mitigated by methylene blue.
RESUMEN
The sodium-glucose-cotransporter 2 inhibitors (SGLT2i) are the blockbuster antidiabetic drugs that exert cardiovascular protection via pleiotropic effects. We have previously demonstrated that empagliflozin decreased monoamine oxidase (MAO) expression and oxidative stress in human mammary arteries. The present study performed in overweight, non-diabetic cardiac patients was aimed to assess whether the two widely prescribed SGLT2i decrease atrial MAO expression and alleviate oxidative stress elicited by exposure to angiotensin 2 (ANG2) and high glucose (GLUC). Right atrial appendages isolated during cardiac surgery were incubated ex vivo with either empagliflozin or dapagliflozin (1, 10 µm, 12 h) in the presence or absence of ANG2 (100 nm) and GLUC (400 mg/dL) and used for the evaluation of MAO-A and MAO-B expression and ROS production. Stimulation with ANG2 and GLUC increased atrial expression of both MAOs and oxidative stress; the effects were significantly decreased by the SGLT2i. Atrial oxidative stress positively correlated with the echocardiographic size of heart chambers and negatively with the left ventricular ejection fraction. In overweight patients, MAO contributes to cardiac oxidative stress in basal conditions and those that mimicked the renin-angiotensin system activation and hyperglycemia and can be targeted with empagliflozin and dapagliflozin, as novel off-target class effect of the SGLT2i.
RESUMEN
Monoamine oxidases (MAOs), mitochondrial enzymes with two isoforms, A and B, have been recently recognized as significant contributors to oxidative stress in the cardiovascular system. The present study was purported to assess the effect of metformin and empagliflozin on MAO expression, oxidative stress and vascular reactivity in internal mammary arteries harvested from overweight patients with coronary heart disease subjected to bypass grafting. Vascular rings were prepared and acutely incubated (12 h) with high glucose (GLUC, 400 mg/dL) or angiotensin II (AII, 100 nM) and metformin (10 µM) and/or empagliflozin (10 µM) and used for the assessment of MAO expression (qRT-PCR and immune histochemistry), reactive oxygen species (ROS, confocal microscopy and spectrophotometry), and vasomotor function (myograph). Ex vivo stimulation with GLUC or AII increased both MAOs expression, ROS production and impaired relaxation to acetylcholine (ACh) of the vascular rings. All effects were alleviated by incubation with each antidiabetic drug; no cumulative effect was obtained when the drugs were applied together. In conclusion, MAO-A and B are upregulated in mammary arteries after acute stimulation with GLUC and AII. Endothelial dysfunction and oxidative stress were alleviated by either metformin or empagliflozin in both stimulated and non-stimulated vascular samples harvested from overweight cardiac patients.