Modifications in nitric oxide and superoxide anion metabolism induced by fructose overload in rat heart are prevented by (−)-epicatechin

Abstract

Fructose overload promotes functional and metabolic derangements in humans and in animal experimental models. Evidence suggests that dietary flavonoids have the ability to prevent/attenuate the development of metabolic diseases. In this work we investigated the effects of (-)-epicatechin on the modifications induced by fructose overload in the rat heart in terms of nitric oxide and superoxide metabolism. Male Sprague Dawley rats received 10% (w/v) fructose in the drinking water for 8 weeks, with or without (-)-epicatechin (20 mg per kg body weight per day) in the rat chow diet. These conditions of fructose overload did not lead to overt manifestations of heart hypertrophy or tissue remodeling. However, biochemical and molecular changes were observed and could represent the onset of functional alterations. (-)-Epicatechin prevented a compromised NO bioavailability and the development of oxidative stress produced by fructose overload essentially acting on superoxide anion metabolism. In this line, the increase in superoxide anion production, the overexpression of NOX2 subunit p47phox and of NOX4, the decrease in superoxide dismutase activity, and the higher oxidized/reduced glutathione ratio installed by fructose overload were absent in the rats receiving (-)-epicatechin. These results support the hypothesis that diets rich in (-)-epicatechin could prevent the onset and progression of heart dysfunctions associated with metabolic alterations.

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…These results are consistent with our previous experiments showing decreased activation of downstream signaling (such as Akt) upon insulin stimulation and significant reduction in insulin-stimulated glucose uptake (Lou et al 2015). At this early stage of insulin resistance, there were no signs of cardiac dysfunction (Table 3) or of cardiac hypertrophy (no increase in atrial natriuretic peptide and a-skeletal muscle actin protein levels, data not shown), confirming previous observations (Calabro et al 2016 Mitochondrial fatty acid oxidation capacity is increased in hearts of early type-2 diabetic fructose-fed rats Levels of nuclear PPARa and PGC1a that transactivate multiple genes involved in myocardial fatty acid utilization were enhanced in hearts of fructose-fed rats (Fig. 1A).…”

“…At this early stage of insulin resistance, there were no signs of cardiac dysfunction (Table 3) or of cardiac hypertrophy (no increase in atrial natriuretic peptide and α ‐skeletal muscle actin protein levels, data not shown), confirming previous observations (Calabro et al. 2016). …”

(-)-Epicatechin protects the intestinal barrier from high fat diet-induced permeabilization: Implications for steatosis and insulin resistance

“…Significantly, we also observed that the permeabilization of Caco-2 monolayers by TNFα was associated with increased NOX1 and NOX4 expression and protein oxidation. As previously observed in other tissues [18] , [20] , [39] , [40] , EC mitigated NADPH oxidase overexpression (NOX1 and NOX4) in HFD-fed mice and Caco-2 cells, and inhibited the enzyme activity in cells. In vitro experiments showing the parallel action of a NADPH oxidase inhibitor (apocynin) and EC preventing TNFα-induced permeabilization and NADPH oxidase overexpression and activity, strongly support ileum epithelial NADPH oxidase as a significant target for the protective actions of EC on HFD-induced intestinal barrier permeabilization in mice.…”

(–)-Epicatechin Modulates Mitochondrial Redox in Vascular Cell Models of Oxidative Stress

“…Here, we observed a suppression of AA-induced mitochondrial superoxide at the higher concentration of EPICAT, albeit not significant, and significant lowering effect of EPI-CAT on HG-induced superoxide, confirming previous studies suggesting that EPICAT is an antioxidant [22,[24][25][26][27][28][29][30][31]38].…”

“…Specifically, EPICAT supports the activation of ROS-regulating transcription factors and decreases ROS in aortic rings and HepG2 cells, measured with immunohistochemistry (IHC) and dihydroethidium (DHE) [24,25]. EPICAT inhibits cardiac, hepatic, adipose, and HepG2 ROS-generating enzymatic or protein expression activity, such as NADPH oxidases (NOXs) and related proteins [26][27][28]. EPICAT has also been shown to alleviate hydrogen peroxide production in damaged cardiac and brain mitochondria by modifying mitochondrial respiration [29].…”