Glucose fluctuations increase the incidence of AF by promoting cardiac fibrosis. Increased ROS levels caused by upregulation of Txnip expression may be a mechanism whereby in glucose fluctuations induce fibrosis.
300TESHIMA Y et al. Circulation JournalOfficial Journal of the Japanese Circulation Society http://www. j-circ.or.jp iabetes mellitus (DM) is an independent risk factor of heart failure. The Framingham Heart Study reported that the frequency of heart failure is 2-fold higher in male diabetics and 5-fold higher in female diabetics than in age-matched control subjects. 1 An increase in reactive oxygen species (ROS) has been regarded as a dominant mechanism of cardiac dysfunction in patients with DM. 2-4 ROS are important intracellular signaling molecules and mediate various cellular functions, including activation of transcriptional factors, protein kinases, and ion channels; however, high levels of ROS are detrimental to cardiomyocytes. In physiological conditions, ROS levels are appropriately controlled by endogenous antioxidant systems to minimize oxidative cellular damage. Oxidative stress occurs when ROS production overwhelms antioxidant capacity in pathological conditions. It is apparent that ROS production and oxidative stress are increased in the diabetic heart, and oxidative stress induces various cardiovascular complications, including cardiac dysfunction, which is facilitated by inflammation, apoptosis, and fibrosis (Figure 1). [5][6][7][8] There is accumulating evidence that mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase play a pivotal role in ROS production in the diabetic heart. In this review, we will summarize the mechanisms of ROS increase in the diabetic heart focusing on the roles of mitochondria and NADPH oxidase. Mitochondria Mitochondrial ROS Production in DMMitochondria not only provide energy, but also provoke apoptosis, which is regulated by mitochondrial dynamics. 9 Mitochondria also generate ROS as natural byproducts of oxygen metabolism in the electron transport chain. Under normal conditions, most of the electrochemical proton gradient is used to generate ATP through ATP synthase, and only 0.1% of the total oxygen consumption leaks from the respiratory chain to generate ROS. However, a high intracellular glucose concentration increases the flux of electron transfer donors (NADH and FADH2) into the mitochondrial respiratory chain by oxidizing glucose-derived pyruvate. The resulting hyperpolarization of the mitochondrial inner membrane potential partially inhibits electron transport in complex III and accumulates electrons to ubisemiquinone to generate superoxide. 10,11 Therefore, mitochondrial respiration is the principal source of ROS in Reactive oxygen species (ROS) are the main facilitators of cardiovascular complications in diabetes mellitus (DM), and the ROS level is increased in cultured cells exposed to high glucose concentrations or in diabetic animal models. Emerging evidence shows that mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are dominant mechanisms of ROS production in the diabetic heart. Hyperpolarization of the mitochondrial inner membrane potentials and impaired mitochondrial function promote ROS production ...
Background Obesity is associated with increased cardiovascular risk; however, the potential role of dysregulations in the adipose tissue (AT) metabolome is unknown. Objectives The aim of this study was to explore the role of dysregulation in the AT metabolome on vascular redox signaling and cardiovascular outcomes. Methods A screen was conducted for metabolites differentially secreted by thoracic AT (ThAT) and subcutaneous AT in obese patients with atherosclerosis (n = 48), and these metabolites were then linked with dysregulated vascular redox signaling in 633 patients undergoing coronary bypass surgery. The underlying mechanisms were explored in human aortic endothelial cells, and their clinical value was tested against hard clinical endpoints. Results Because ThAT volume was associated significantly with arterial oxidative stress, there were significant differences in sphingolipid secretion between ThAT and subcutaneous AT, with C16:0-ceramide and derivatives being the most abundant species released within adipocyte-derived extracellular vesicles. High ThAT sphingolipid secretion was significantly associated with reduced endothelial nitric oxide bioavailability and increased superoxide generated in human vessels. Circulating C16:0-ceramide correlated positively with ThAT ceramides, dysregulated vascular redox signaling, and increased systemic inflammation in 633 patients with atherosclerosis. Exogenous C16:0-ceramide directly increased superoxide via tetrahydrobiopterin-mediated endothelial nitric oxide synthase uncoupling and dysregulated protein phosphatase 2 in human aortic endothelial cells. High plasma C16:0-ceramide and its glycosylated derivative were independently related with increased risk for cardiac mortality (adjusted hazard ratios: 1.394; 95% confidence interval: 1.030 to 1.886; p = 0.031 for C16:0-ceramide and 1.595; 95% confidence interval: 1.042 to 2.442; p = 0.032 for C16:0-glycosylceramide per 1 SD). In a randomized controlled clinical trial, 1-year treatment of obese patients with the glucagon-like peptide-1 analog liraglutide suppressed plasma C16:0-ceramide and C16:0-glycosylceramide changes compared with control subjects. Conclusions These results demonstrate for the first time in humans that AT-derived ceramides are modifiable regulators of vascular redox state in obesity, with a direct impact on cardiac mortality in advanced atherosclerosis. (The Interaction Between Appetite Hormones; NCT02094183 )
Aims Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans. Methods and results Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide (O2.−) sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with O2.− production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM. Conclusions We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin.
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