This study highlights the importance of extracellular nucleotides and adenosine metabolism in the atherosclerotic vessel in both experimental and clinical setting. The increased eADA activity marks an early stage of atherosclerosis, contributes to its progression and could represent a novel target for therapy.
1-Methylnicotinamide (MNA), the major endogenous metabolite of nicotinic acid (NicA), may partially contribute to the vasoprotective properties of NicA. Here we compared the antiatherosclerotic effects of MNA and NicA in apolipoprotein E (ApoE)/ low-density lipoprotein receptor (LDLR)-deficient mice. ApoE/ LDLR 2/2 mice were treated with MNA or NicA (100 mg/kg). Plaque size, macrophages, and cholesterol content in the brachiocephalic artery, endothelial function in the aorta, systemic inflammation, platelet activation, as well as the concentration of MNA and its metabolites in plasma and urine were measured. MNA and NicA reduced atherosclerotic plaque area, plaque inflammation, and cholesterol content in the brachiocephalic artery. The antiatherosclerotic actions of MNA and NicA were associated with improved endothelial function, as evidenced by a higher concentration of 6-keto-prostaglandin F 1a and nitrite/nitrate in the aortic ring effluent, inhibition of platelets (blunted thromboxane B 2 generation), and inhibition of systemic inflammation (lower plasma concentration of serum amyloid P, haptoglobin). NicA treatment resulted in an approximately 2-fold higher concentration of MNA and its metabolites in urine and a 4-fold higher nicotinamide/MNA ratio in plasma, compared with MNA treatment. In summary; MNA displays pronounced antiatherosclerotic action in ApoE/LDLR 2/2 mice, an effect associated with an improvement in prostacyclin-and nitric oxide-dependent endothelial function, inhibition of platelet activation, inhibition of inflammatory burden in plaques, and diminished systemic inflammation. Despite substantially higher MNA availability after NicA treatment, compared with an equivalent dose of MNA, the antiatherosclerotic effect of NicA was not stronger. We suggest that detrimental effects of NicA or its metabolites other than MNA may limit beneficial effects of NicA-derived MNA.
Edited by: Philip Atherton New Findings r What is the central question of this study?The main aim of the present study was to determine the effect of prolonged moderate-intensity endurance training on the endothelial glycocalyx layer integrity in relationship to the training-induced changes in oxidative stress and antioxidant defence in humans. r What is the main finding and its importance?We have shown, for the first time, a protective effect of prolonged moderate-intensity endurance training on endothelial glycocalyx layer integrity, as judged by significantly lower basal and end-exercise serum concentrations of glycocalyx damage markers, i.e. syndecan-1 and heparan sulfate, accompanied by attenuation of oxidative stress and enhancement of antioxidant defence after training in previously untrained healthy young men.In this study, we evaluated the effect of 20 weeks of moderate-intensity endurance training (ET) on the endothelial glycocalyx layer integrity in relationship to the training-induced changes in antioxidant defence. Eleven healthy young, untrained men performed an incremental cycling exercise bout until exhaustion before and after 20 weeks of ET. Endurance training consisted of 40 min sessions, mainly of moderate intensity (ß50% of maximal oxygen uptake), performed four times per week. Venous blood samples were taken at rest and at the end of the maximal exercise test. Muscle biopsies from vastus lateralis were taken before and after the training. Endurance training resulted in a significant increase in physical capacity (P < 0.05) as reflected by an increase in power output reached at the lactate threshold and at maximal oxygen uptake. Training led to a decrease (P < 0.05) in basal and end-exercise concentrations of blood markers of glycocalyx damage (syndecan-1 and heparan sulfate). The lowering of glycocalyx shedding after the ET was accompanied by an attenuation of oxidative stress, as evidenced by a decrease in the basal plasma concentration of isoprostanes, and by an increase in antioxidant defence, reflected by an enhancement in superoxide dismutase 2 protein content in vastus lateralis (P < 0.05). In contrast, training did not induce a significant increase in basal nitrite/nitrate 71 Endurance training and endothelial glycocalyx integrity plasma concentration (P > 0.05). Moderate-intensity ET exerts a pronounced protective effect on endothelial glycocalyx integrity at rest and during exercise, probably through an improvement of antioxidant defence that may represent the vasoprotective mechanisms highly responsive to moderate-intensity endurance training.
BackgroundThe early detection of metastasis based on biomarkers in plasma may improve cancer prognosis and guide treatment. The aim of this work was to characterize alterations in metabolites of the arginine pathway, energy metabolism, and structural and signalling lipids in plasma in the early and late stages of murine breast cancer metastasis.MethodsMice were orthotopically inoculated with 4T1 metastatic breast cancer cells, and plasma was analysed along the pulmonary metastasis progression using LC-MS/MS-based targeted metabolomics and lipidomics.ResultsBased on primary tumour growth and pulmonary metastases, 1–2 weeks after 4T1 cancer cell inoculation was defined as an early metastatic stage, and 3–4 weeks after 4T1 cancer cell inoculation was defined as a late metastatic stage. Early metastasis was featured in plasma by a shift of L-arginine metabolism towards arginase (increased ornithine/arginine ratio) and polyamine synthesis (increased putrescine). Late metastasis was reflected in plasma by further progression of changes in the arginine pathway with an additional increase in asymmetric dimethylarginine plasma concentration, as well as by a profound energy metabolism reprogramming towards glycolysis, an accelerated pentose phosphate pathway and a concomitant decrease in tricarboxylic cycle rate (“Warburg effect”). The late but not the early phase of metastasis was also characterized by a different lipid profile pattern in plasma, including a decrease in total phosphatidylcholines, a decrease in diester-bound phospholipid fraction and an increase in lysophospholipids associated with an increase in total sphingomyelins.ConclusionsThe early phase of metastasis in murine 4T1 metastatic breast cancer was associated with plasma metabolome changes characteristic of arginase activation and polyamine synthesis. The late metastasis was reflected in plasma not only by the alterations in arginine pathways but also by a shift towards glycolysis and the pentose pathway, remodelling of structural lipids and activation of lipid signalling, all of which coincided with metastasis progression.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1075-y) contains supplementary material, which is available to authorized users.
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