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Changes in metabolites and lipid mediators associated with supervised exercise training for peripheral

ABSTRACT: Peripheral artery disease (PAD) is a leading cause of cardiovascular related morbidity and mortality, affecting over 8.5 million men and women in the United States and greater than 200 million individuals worldwide. The mainstay of treatment to improve lower limb symptoms is supervised walking therapy, which does not affect plaque morphology or alter conduit artery blood flow, but rather ameliorates endothelial dysfunction, enhances skeletal muscle metabolism and mitochondrial function, and suppresses inflammatory activation. In this pilot feasibility project we will employ metabolic and lipidomic techniques to measure the effects of supervised exercise therapy on primary metabolism, complex lipids, and lipid mediators, and correlate these effects with individual, subject-level measures of the response to exercise therapy among subjects with PAD. The overarching theme of this work is to identify metabolites, complex lipids, and lipid mediators that are associated with the inter-individual variability in the response of subjects with PAD to supervised exercise therapy. This knowledge will significantly enhance our understanding of the pathophysiology of lower extremity symptoms in PAD, as well as the manner in which supervised exercise therapy improves walking intolerance. It will identify novel therapeutic targets and pathways for pharmacologic manipulation in the treatment of PAD. Aside from having the potential to generate multiple high-impact publications, it will serve as the basis for a planned NIH R01 submission by the PI at the conclusion of the award period.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Blood

DISEASE(S): Peripheral Artery Disease

SUBMITTER: John Newman

PROVIDER: ST000659 | MetabolomicsWorkbench | Wed Jun 28 00:00:00 BST 2017

REPOSITORIES: MetabolomicsWorkbench

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Project description:Background: Endothelial cells (ECs) use glycolysis to produce energy. In pre-clinical models of peripheral arterial disease (PAD), the further activation of EC glycolysis was ineffective and/or deleterious in promoting hypoxia-dependent angiogenesis while pentose phosphate pathway (PPP) activation was effective. Hexosamine biosynthesis pathway (HBP), PPP, and glycolysis are closely linked. Glucosamine directly activates HBP.Methods:Hind-limb ischemia (HLI)ineNOS-/-and Balb/c mice was used. Glucosamine (600 ug/g/day) was injected intraperitoneally. Blood flow recovery was assessed using laser Doppler perfusion imaging (LDPI), angiogenesis was studied by CD31immunostaining.In-vitro: human umbilical vein ECs (HUVECs) and mouse microvascular EC with glucosamine, L-glucose or vascular endothelial growth factor (VEGF165a), were tested underhypoxiaand serum starvation (HSS). Cell counting kit-8 (CCK-8), tube formation, intracellular reactive oxygen species (ROS), Electric Cell-substrate Impedance Sensing (ECIS) and FITC dextran permeability were assessed. Glycolysis and oxidative phosphorylation were assessed by seahorse assay. Gene expression was assessed using RNA sequencing, real-time qPCR, and western blot. Human muscle biopsies from patients with PAD were assessed for EC O-GlcNAcylation before and after supervised exercise vs. standard medical care. Results: Day-3 post-HLI,glucosamine vs. control-treated eNOS-/-had less necrosis.Beginning Day-7 post-HLI, glucosamine vs. control-treated Balb/chad higherblood flowthat persisted to Day-21whereischemic musclesshowed greaterCD31 staining/muscle fiber. In-vitro,glucosamine vs. L-glucoseshowedimproved EC survival and tube formation. RNA-sequencing of glucosamine vs. L-glucose showed increased amino acid metabolism. That resulted in increased oxidative phosphorylation and serine biosynthesis pathway (SBP) without an increase in glycolysis or PPP genes. This was associated with better barrier function and less ROS compared to activating glycolysis by VEGF165a. These effects were mediated by activating transcription factor 4 (ATF4); a driver of exercise-induced angiogenesis. Finally, in muscle biopsies from humans with PAD,EC/O-GlcNAcylation was increased by 12 weeks of supervised exercise vs. standard medical care. Conclusion: In-cells, mice, and humans activation of HBP by glucosamine in PAD inducesan “exercise-like” angiogenesis and offers a promising novel therapeutic pathway to treat this challenging disorder.

Project description:Background: Lower-limb peripheral artery disease (PAD) is one of the major complications of diabetes mellitus. PAD is associated with poor limb and cardiovascular prognoses, along with a dramatic decrease in life expectancy. Despite major medical advances in the treatment of diabetes, a substantial therapeutic gap remains in the PAD population. Praliciguat is an orally available soluble guanylate cyclase (sGC) stimulator that has been reported both pre-clinically and in early-stage clinical trials to have favorable effects in metabolic and hemodynamic outcomes, suggesting that it may have a potential beneficial effect in PAD. Objective: We evaluated the effect of praliciguat on hind limb ischemia (HLI) recovery in a mouse model of type 2 diabetes. Methods: HLI was induced in leptin receptor-deficient (Leprdb/db) mice by ligation and excision of the left femoral artery. Praliciguat (10 mg/kg/day) was administered in the diet starting 3 days before surgery. Results: 28 days after surgery, ischemic foot perfusion and function parameters were better in praliciguat-treated mice than in vehicle controls. Improved ischemic foot perfusion was not associated with either improved traditional cardiovascular risk factors (i.e., weight, glycemia) or increased angiogenesis. However, treatment with praliciguat significantly increased arteriole diameter, decreased intercellular adhesion molecule 1 (ICAM1) expression, and prevented the accumulation of oxidative pro-angiogenic and pro-inflammatory muscle fibers. While investigating the mechanism underlying the beneficial effects of praliciguat therapy, we found that praliciguat significantly downregulated Myh2 and Cxcl12 mRNA expression in cultured myoblasts and that conditioned medium form praliciguat-treated myoblast decreased ICAM-1 mRNA expression in endothelial cells. These results suggest that praliciguat therapy may decrease ICAM-1 expression in endothelial cells by downregulating Cxcl12 in myocytes. Conclusion: Our results demonstrated that praliciguat promotes blood flow recovery in the ischemic muscle of mice with type 2 diabetes, at least in part by increasing arteriole diameter and by downregulating ICAM-1 expression.

Project description:Individuals affected by post-covid condition (PCC) show an increased fatigue and the so-called post-exertion malaise (PEM) that led health professionals to advise against exercise although accumulating evidence indicate the contrary. The goal of this study is to determine the impact of a closely monitored 8-week mixed exercise program on physical capacity, symptoms, fatigue, systemic oxidative stress and plasma proteomic profiles of PCC cases. Methods: Twenty-five women and men with PCC assigned sequentially to exercise (n = 15) and non-exercise (n = 10) groups. Individuals with no PCC served as a control group. The exercise program included cardiovascular and resistance exercises. Physical capacity, physical activity level and the presence of common PCC symptoms were measured before and after the intervention. Fatigue was measured the day following each exercise session. Plasma and PBMC samples were collected at the beginning and end of the training program. Glutathione and deoxyguanosine levels in PBMC and plasma proteomic profiles were evaluated. Results: Bicep Curl (p=0.040) and STS-30 (p=0.043) improved to a greater extent in the exercise group than in the non-exercise group. An interaction effect was also observed for the level of physical activity (p=0.007) with a positive effect of the program on their daily functioning and without any adverse effects on general or post-effort fatigue. Glutathione levels showed marked improvement after exercise. Discernable changes were observed in the plasma proteomics profile with certain proteins involved in inflammatory response (SA100A8) decreasing in the exercise group. Conclusion: Supervised exercise adapted to the level of fatigue and ability is safe and effective in PCC patients in improving their general physical capacity and wellbeing. Systemic molecular markers that accompany physical improvement can be monitored by analyzing plasma proteomics and markers of oxidative stress. Large-scale studies will help identify promising molecular markers to objectively monitor patient improvement.

Project description:While the salutary effects of exercise training on conduit artery endothelial cells have been reported in animals and humans with cardiovascular risk factors or disease, whether a healthy endothelium is alterable with exercise training is less certain. The purpose of this study was to evaluate the impact of exercise training on transcriptional profiles in normal endothelial cells using a genome-wide microarray analysis. Brachial and internal mammary endothelial gene expression was compared between a group of healthy pigs that exercise-trained for 16-20 weeks (n=8) and a group that remained sedentary (n=8). We found that a total of 130 genes were up regulated and 84 genes down regulated in brachial artery endothelial cells with exercise training. In contrast, a total of 113 genes were up regulated and 31 genes down regulated in internal mammary artery endothelial cells (>1.5-fold and false discovery rate<15%). Although there was an overlap of 66 genes (59 up regulated and 7 down regulated with exercise training) between the brachial and internal mammary arteries, the identified endothelial gene networks and biological processes influenced by exercise training were distinctly different between the brachial and internal mammary arteries. These data indicate that a healthy endothelium is indeed responsive to exercise training and support the concept that the influence of physical activity on endothelial gene expression is not homogenously distributed throughout the vasculature. Brachial and internal mammary endothelial gene expression was compared between a group of healthy pigs that exercise-trained for 16-20 weeks (n=8) and a group that remained sedentary (n=8). The arteries were taken from the same animals, and after quality assessment, so there were 29 total arrays (15 unique pigs), 14 with an array for both the brachial artery and the internal mammary artery (IMA), and the remaining 1 having only brachial. One pig had bad RNA quality and is missing from both IMA and brachical. Therefore, there were 15 IMA (7 SED, 8 EX) and 14 brachial arrays (7 SED, 7 EX) that were used in this study.

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