EFFECTS OF CARDIOVASCULAR DISEASE AND PHYSICAL INACTIVITY ON THE PARACRINE FUNCTION OF CIRCULATING ANGIOGENIC CELLS

Cardiovascular disease (CVD) is the leading cause of death in developed countries. Traditional cardiovascular risk factors account for only a fraction of events related to CVDs, emphasizing the need for investigations into more novel risk factors. Circulating angiogenic cells (CACs) are involved in the repair and maintenance of the vascular endothelium and function mainly through paracrine mechanisms. The studies presented in this dissertation provide new insight into differences in the paracrine actions of CACs as a function of habitual physical activity and CVD. The first study presented identifies, for the first time, that secreted factors from CD34+ and CD34-/CD31+ CACs affect HUVEC tube formation as a function of habitual physical activity. Study #1 identifies inflammatory proteins S100A8 and S100A9 as major factors contributing to the depressed tube formation observed when using CD34-/CD31+ conditioned media (CM) from inactive younger adults compared to endurance-trained athletes. The second study aimed to confirm the effects of S100A8 and S100A9 in CD34-/CD31+ CM on HUVEC tube formation in CVD patient populations compared to endurance-trained athletes. Study #2 found that the CM from non-ST- segment elevation myocardial infarction (NSTEMI) patient CD34-/CD31+ CACs impaired tube formation compared to athletes’ CM, and that pretreatment of HUVECs with an inhibitor for TLR4, a major receptor for S100A8 and S100A9, rescued tube formation to the levels observed when using CD34-/CD31+ CM from athletes. Higher S100A8 and S100A9 content was found in the CM of NSTEMIs compared to athletes. Finally, the study #2 mechanistically demonstrated the direct role of S100A8 and S100A9 on tube formation using recombinant S100A8 and S100A9 and confirmed that these actions were mediated by TLR4. Preliminary data in study #2 suggest that cell surface markers on selected CD34-/CD31+ CACs are inherently different between NSTEMI patients and endurance-trained athletes with lower presence of T-cell and monocyte markers on the CD34-/CD31+ CACs of NSTEMI patients. Collectively, the two studies presented in this dissertation demonstrate that both physical inactivity and CVD alter the paracrine actions of CD34-/CD31+ CACs which in turn impair HUVEC tube formation. These findings are of particular importance as new methods to improve CAC function for therapeutic purposes are being developed

Effects of Prior Acute Exercise on Circulating Cytokine Concentration Responses to a High-fat Meal

High-fat meal consumption alters the circulating cytokine profile and contributes to cardiometabolic diseases. A prior bout of exercise can ameliorate the triglyceride response to a high-fat meal, but the interactive effects of exercise and high-fat meals on cytokines that mediate cardiometabolic risk are not fully understood. We investigated the effects of prior exercise on the responses of circulating tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), IL-8, leptin, retinol-binding protein 4 (RBP4), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1) to a high-fat meal. Ten healthy men were studied before and 4 h after ingestion of a high-fat meal either with or without ~50 min of endurance exercise at 70% of VO2 max on the preceding day. In response to the high-fat meal, lower leptin and higher VEGF, bFGF, IL-6, and IL-8 concentrations were evident (P \u3c 0.05 for all). There was no effect of the high-fat meal on PlGF, TNF-a, or RBP4 concentrations. We found lower leptin concentrations with prior exercise (P \u3c 0.05) and interactive effects of prior exercise and the high-fat meal on sFlt-1 (P \u3c 0.05). The high-fat meal increased IL-6 by 59% without prior exercise and 218% with prior exercise (P \u3c 0.05). In conclusion, a prior bout of endurance exercise does not affect all high-fat meal–induced changes in circulating cytokines, but does affect fasting or postprandial concentrations of IL-6, leptin, and sFlt-1. These data may reflect a salutary effect of prior exercise on metabolic responses to a high-fat meal

Comparison of Near-Infrared Spectroscopy Measured Muscle Metabolism with Predicted Whole-Body Metabolism

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Establishing the Reproducibility of Mitochondrial Capacity using Near-Infrared Spectroscopy

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The Effects of 50k Ultramarathon Running on Quadriceps Torque and Circulating Inflammatory Calprotectin

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Aerobic Capacity Independently Predicts Central Augmentation Index Among Apparently Healthy Adults

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Endothelial Function is Preserved in Ultra-Marathon Runners Following a 50 km Race

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Changes in Circulating Angiogenic Cell Number and Function During and After an Ultramarathon

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