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  • ddhUTP structure In tumor cells HK II induction


    In tumor cells HK-II induction is mediated by Akt/mTOR pathway [6], [11]. HK-II dynamically shuttles between the mitochondria and cytoplasm under different metabolic conditions. In cardiomyocytes, Akt enhances HK-II binding to mitochondria, setting the heart at a state resistant to ischemic injury [12]. Akt is a serine/threonine kinase with the activity to regulate diverse functions including glucose metabolism, cellular growth and survival. Akt inhibits cell apoptosis by regulation of glycolysis and mitochondrial hexokinase [13]. HK-II contains an Akt consensus sequence, indicating the potency to be regulated by Akt [8]. Consistent with this, D.J. Roberts and colleagues show that Akt phosphorylates HK-II at Thr-473, promoting HK-II binding to mitochondria [14]. These events suggest that phosphorylation of HK-II by Akt activation might be a therapeutical target in the protection of mitochondrial function. Mangiferin is a xanthonoid abundant in plants such as mangoes and Iris unguicularis with a wide range of bioactivities. Mangiferin exerts anti-diabetic action with the ability to improve lipid profiles in experimental animals [15], [16], demonstrating well its beneficial effects on metabolic homeostasis. Our previous work also shows that mangiferin ameliorates endothelial dysfunction by suppressing ER stress, indicating its potential role in the protection of vessel function [17]. In the present study, we investigated the effect of mangiferin on mitochondrial function in vessel endothelial cells with emphasis on the regulation of HK-II binding to mitochondria. Our work showed that mangiferin prevented mitochondrial dysregulation by promoting HK-II binding to mitochondria via Akt activation. This finding indicates that pharmacological activation of Akt might be a novel therapeutical strategy for the protection of mitochondrial function in the endothelium.
    Materials and methods
    Discussion Endothelial dysfunction is an early event in the development of cardiovascular diseases. Endothelial dysfunction in the renal vasculature is implicated in ischemic kidney injury and impaired endothelium-dependent vasodilation of the coronary microcirculation is associated with myocardial ischemia [21], [22]. In brain, the cerebral endothelial cells are the primary target of hypoxic or ischemic ddhUTP structure insults [23]. Because lipid disorder-induced endothelial impairment mainly occurs in the large artery, we observed the effect of mangiferin on endothelial function in endothelial cells derived from rat aorta in the setting of saturated acid challenge. Saturated fatty acid overload altered cellular metabolism, indicated by increased lactate accumulation in endothelial cells. PDH converts pyruvate to acetyl CoA for mitochondrial oxidation in the citric acid cycle (CAC) and thereby occupies a critical link between glycolysis and glucose oxidation. Enhanced fatty acid oxidation could inhibit glucose oxidation, a regulation referred to as the Randle Cycle [24]. Consistent with this, we observed that PA challenge impaired PDH activity and increased lactate accumulation due to uncoupling glycolysis from oxidation. Mitochondrial HK-II is susceptible to cellular acidification [9]. Mangiferin reduced lactate accumulation by improving PDH activity, and this action should contribute to preserve HK-II binding to mitochondria due to the improved cellular homeostasis. Indeed, mangiferin prevented HK-II detachment from mitochondria in endothelial cells subjected to PA insult. This result also indicated that the alternation of mitochondrial oxidation and increased redox state are pathological causes for the dissociation of HK-II from mitochondria. Akt is usually considered a survival factor because it promotes cell survival via the negative regulation of the proapoptotic proteins [25]. Akt is normally maintained in an inactive state, and in response to activation Akt traverses the cell interior with regulated localization [26]. Consistent with this, we observed that mangiferin activated Akt by phosphorylation and increased Akt translocation to mitochondria where it joined together with HK-II to increase mitochondrial binding. As expected, mangiferin prevented HK-II detachment from mitochondria and reduced HK-II release into the cytosol in endothelial cells exposed to PA challenge, well demonstrating its action in promoting HK-II association with mitochondria. Akt inhibitor triciribine and knockdown of Akt blocked mangiferin action in the protection of mitochondrial HK-II, indicating that mangiferin promoted HK-II binding to mitochondria via regulation of Akt activation. It has been documented that Akt increases mitochondrial HK-II association via direct phosphorylation of HK-II in cardiomyocytes [14], and consistent with this, our work further confirmed the regulation in vessel endothelial cells.