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Veves, Aristidis

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Veves

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Aristidis

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Veves, Aristidis
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Now showing 1 - 9 of 9
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    Molecular Biomarkers of Vascular Dysfunction in Obstructive Sleep Apnea
    (Public Library of Science, 2013) Kaczmarek, Elzbieta; Bakker, Jessie; Clarke, Douglas N.; Csizmadia, Eva; Kocher, Olivier; Veves, Aristidis; Tecilazich, Francesco; O'Donnell, Christopher P.; Ferran, Christiane; Malhotra, Atul
    Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro)vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1α?? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]<75%) compared to mildly hypoxemic OSA patients (SaO2 75%–90%) and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1) expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1α expression in HMVEC, while increased A20, VCAM-1 and HIF-1αexpression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients.
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    Mechanisms Involved in the Development and Healing of Diabetic Foot Ulceration
    (American Diabetes Association, 2012) Dinh, Thanh; Tecilazich, Francesco; Kafanas, Antonios; Doupis, John; Gnardellis, Charalambos; Leal, Ermelindo; Tellechea, Ana; Pradhan, Leena; Lyons, Thomas E.; Giurini, John; Veves, Aristidis
    We examined the role of vascular function and inflammation in the development and failure to heal diabetic foot ulcers (DFUs). We followed 104 diabetic patients for a period of 18.4 ± 10.8 months. At the beginning of the study, we evaluated vascular reactivity and serum inflammatory cytokines and growth factors. DFUs developed in 30 (29%) patients. DFU patients had more severe neuropathy, higher white blood cell count, and lower endothelium-dependent and -independent vasodilation in the macrocirculation. Complete ulcer healing was achieved in 16 (53%) patients, whereas 13 (47%) patients did not heal. There were no differences in the above parameters between the two groups, but patients whose ulcers failed to heal had higher tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metallopeptidase 9 (MMP-9), and fibroblast growth factor 2 serum levels when compared with those who healed. Skin biopsy analysis showed that compared with control subjects, diabetic patients had increased immune cell infiltration, expression of MMP-9, and protein tyrosine phosphatase-1B (PTP1B), which negatively regulates the signaling of insulin, leptin, and growth factors. We conclude that increased inflammation, expression of MMP-9, PTP1B, and aberrant growth factor levels are the main factors associated with failure to heal DFUs. Targeting these factors may prove helpful in the management of DFUs.
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    Role of Endothelial Progenitor Cells and Inflammatory Cytokines in Healing of Diabetic Foot Ulcers
    (Public Library of Science, 2013) Tecilazich, Francesco; Dinh, Thanh; Pradhan-Nabzdyk, Leena; Leal, Ermelindo; Tellechea, Ana; Kafanas, Antonios; Gnardellis, Charalambos; Magargee, Mary L.; Dejam, Andre; Toxavidis, Vasilis; Tigges, John C.; Carvalho, Eugenia; Lyons, Thomas E.; Veves, Aristidis
    Background: To evaluate changes in endothelial progenitor cells (EPCs) and cytokines in patients with diabetic foot ulceration (DFU) in association with wound healing. Methods: We studied healthy subjects, diabetic patients not at risk of DFU, at risk of DFU and with active DFU. We prospectively followed the DFU patients over a 12-week period. We also investigated similar changes in diabetic rabbit and mouse models of wound healing. Results: All EPC phenotypes except the kinase insert domain receptor (KDR)+CD133+ were reduced in the at risk and the DFU groups compared to the controls. There were no major EPC differences between the control and not at risk group, and between the at risk and DFU groups. Serum stromal-cell derived factor-1 (SDF-1) and stem cell factor (SCF) were increased in DFU patients. DFU patients who healed their ulcers had lower CD34+KDR+ count at visits 3 and 4, serum c-reactive protein (CRP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) at visit 1, interleukin-1 (IL-1) at visits 1 and 4. EPCs tended to be higher in both diabetic animal models when compared to their non-diabetic counterparts both before and ten days after wounding. Conclusions: Uncomplicated diabetes does not affect EPCs. EPCs are reduced in patients at risk or with DFU while complete wound healing is associated with CD34+KDR+ reduction, suggesting possible increased homing. Low baseline CRP, IL-1α and GM-CSF serum levels were associated with complete wound healing and may potentially serve as prognostic markers of DFU healing. No animal model alone is representative of the human condition, indicating the need for multiple experimental models.
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    Genome-wide DNA methylation analysis identifies a metabolic memory profile in patient-derived diabetic foot ulcer fibroblasts
    (Taylor & Francis, 2014) Park, Lara K; Maione, Anna G; Smith, Avi; Gerami-Naini, Behzad; Iyer, Lakshmanan K; Mooney, David; Veves, Aristidis; Garlick, Jonathan A
    Diabetic foot ulcers (DFUs) are a serious complication of diabetes. Previous exposure to hyperglycemic conditions accelerates a decline in cellular function through metabolic memory despite normalization of glycemic control. Persistent, hyperglycemia-induced epigenetic patterns are considered a central mechanism that activates metabolic memory; however, this has not been investigated in patient-derived fibroblasts from DFUs. We generated a cohort of patient-derived lines from DFU fibroblasts (DFUF), and site- and age-matched diabetic foot fibroblasts (DFF) and non-diabetic foot fibroblasts (NFF) to investigate global and genome-wide DNA methylation patterns using liquid chromatography/mass spectrometry and the Illumina Infinium HumanMethylation450K array. DFFs and DFUFs demonstrated significantly lower global DNA methylation compared to NFFs (p = 0.03). Hierarchical clustering of differentially methylated probes (DMPs, p = 0.05) showed that DFFs and DFUFs cluster together and separately from NFFs. Twenty-five percent of the same probes were identified as DMPs when individually comparing DFF and DFUF to NFF. Functional annotation identified enrichment of DMPs associated with genes critical to wound repair, including angiogenesis (p = 0.07) and extracellular matrix assembly (p = 0.035). Identification of sustained DNA methylation patterns in patient-derived fibroblasts after prolonged passage in normoglycemic conditions demonstrates persistent metabolic memory. These findings suggest that epigenetic-related metabolic memory may also underlie differences in wound healing phenotypes and can potentially identify therapeutic targets.
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    Diabetic Peripheral Neuropathy as a Predictor of Asymptomatic Myocardial Ischemia in Type 2 Diabetes Mellitus: A Cross-Sectional Study
    (Springer Healthcare, 2016) Baltzis, Dimitrios; Roustit, Matthieu; Grammatikopoulou, Maria G.; Katsaboukas, Dimitrios; Athanasiou, Vassileios; Iakovou, Ioannis; Veves, Aristidis; Manes, Christos; Trakatelli, Maria-Christina
    Introduction: Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes and has been associated with cardiovascular disease, the leading cause of mortality in diabetes. As asymptomatic myocardial ischemia (MI) is frequent in diabetes, we hypothesized that DPN may be associated with MI in patients with type 2 diabetes mellitus and no history of cardiovascular events. Methods: Eighty-two patients with DPN (n = 41) or without DPN (n = 41) were included. Among the DPN group, 15 had active foot ulcers. All subjects underwent Technetium-99 m sestamibi single-photon emission computed tomographic imaging for the estimation of myocardial ischemia, expressed as Summed Stress Score (SSS). The Neuropathy Disability Score (NDS) was used to quantify DPN and abnormal ratio of the longest electrocardiographic RR interval between the 28th and 32nd beats, after standing to the shortest interval between the 13th and 17th beats (RR ratio) was used as an index of cardiovascular autonomic neuropathy (CAN). Results: Abnormal SSS was observed in 9.8% of patients without DPN and in 46.3% of patients with DPN (p < 0.001). In the multivariate analysis, NDS was the strongest predictor for SSS (β = 0.32, p = 0.003). When excluding patients with abnormal RR ratio (β = 0.32, p = 0.003) or with foot ulcers (β = 0.24, p = 0.04), this association remained significant. The RR ratio was also significantly associated with SSS in univariate (ρ = −0.30, p = 0.005) and multiple regressions (β = 0.24, p = 0.02). Conclusions: MI was strongly associated with DPN, and this association remained significant in patients with normal RR ratio. These results suggest that DPN assessment could help in identifying patients at risk of cardiovascular disease (CVD). Electronic supplementary material The online version of this article (doi:10.1007/s12325-016-0399-1) contains supplementary material, which is available to authorized users.
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    Protocol for a Systematic Review and Individual Patient Data Meta-analysis of Prognostic Factors of Foot Ulceration in People with Diabetes: The International Research Collaboration for the Prediction of Diabetic Foot Ulcerations (PODUS).
    (Springer (Biomed Central Ltd.), 2013) Crawford, Fay; Anandan, Chantelle; Chappell, Francesca M; Murray, Gordon D; Price, Jacqueline F; Sheikh, Aziz; Simpson, Colin R; Maxwell, Martin; Stansby, Gerard P; Young, Matthew J; Abbott, Caroline A; Boulton, Andrew JM; Boyko, Edward J; Kastenbauer, Thomas; Leese, Graham P; Monami, Matteo; Monteiro-Soares, Matilde; Rith-Najarian, Stephen J; Veves, Aristidis; Coates, Nikki; Jeffcoate, William J; Leech, Nicola; Fahey, Tom; Tierney, Jayne
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    Impaired Distal Thermoregulation in Diabetes and Diabetic Polyneuropathy
    (American Diabetes Association, 2009) Rutkove, Seward; Veves, Aristidis; Mitsa, Theophano; Nie, Rui; Fogerson, Patricia M.; Garmirian, Lindsay P.; Nardin, Rachel
    Objective: To determine how thermoregulation of the feet is affected by diabetes and diabetic polyneuropathy in both wakefulness and sleep. Research Design and Methods: Normal subjects, diabetic subjects without neuropathy, diabetic subjects with small-fiber diabetic polyneuropathy, and those with advanced diabetic polyneuropathy were categorized based on neurological examination, nerve conduction studies, and quantitative sensory testing. Subjects underwent foot temperature monitoring using an iButton device attached to the foot and a second iButton for recording of ambient temperature. Socks and footwear were standardized, and subjects maintained an activity diary. Data were collected over a 32-h period and analyzed. Results: A total of 39 normal subjects, 28 patients with diabetes but without diabetic polyneuropathy, 14 patients with isolated small-fiber diabetic polyneuropathy, and 27 patients with more advanced diabetic polyneuropathy participated. No consistent differences in foot temperature regulation between the four groups were identified during wakefulness. During sleep, however, multiple metrics revealed significant abnormalities in the diabetic patients. These included reduced mean foot temperature (P < 0.001), reduced maximal temperature (P < 0.001), increased rate of cooling (P < 0.001), as well as increased frequency of variation (P = 0.005), supporting that patients with diabetic polyneuropathy and even those with only diabetes but no diabetic polyneuropathy have impaired nocturnal thermoregulation. Conclusions: Nocturnal foot thermoregulation is impaired in patients with diabetes and diabetic polyneuropathy. Because neurons are highly temperature sensitive and because foot warming is part of the normal biology of sleep onset and maintenance, these findings suggest new potentially treatable mechanisms of diabetes-associated nocturnal pain and sleep disturbance.
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    O-Glycosylation Regulates Ubiquitination and Degradation of the Anti-Inflammatory Protein A20 to Accelerate Atherosclerosis in Diabetic ApoE-Null Mice
    (Public Library of Science, 2010) Shrikhande, Gautam V.; Scali, Salvatore T.; Csizmadia, Eva; Matthey, Michaela; Arjoon, Roy; Patel, Rakesh; Maccariello, Elizabeth R.; Andersen, Nicholas D.; Monahan, Thomas; Studer, Peter; Padilha Guedes, Renata; Usheva, Anny; Da Silva, Cleide; Damrauer, Scott Michael; Putheti, P; Siracuse, Jeffrey Joseph; Peterson, Clayton Ross; Essayagh, Sanah; Kocher, Olivier; Veves, Aristidis; Kaczmarek, Elzbieta; Ferran, Christiane
    Background: Accelerated atherosclerosis is the leading cause of morbidity and mortality in diabetic patients. Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete. Methodology/Principal Findings: High glucose and hyperglycemia reduced upregulation of the NF-κB inhibitory and atheroprotective protein A20 in human coronary endothelial (EC) and smooth muscle cell (SMC) cultures challenged with Tumor Necrosis Factor alpha (TNF), aortae of diabetic mice following Lipopolysaccharide (LPS) injection used as an inflammatory insult and in failed vein-grafts of diabetic patients. Decreased vascular expression of A20 did not relate to defective transcription, as A20 mRNA levels were similar or even higher in EC/SMC cultured in high glucose, in vessels of diabetic C57BL/6 and FBV/N mice, and in failed vein grafts of diabetic patients, when compared to controls. Rather, decreased A20 expression correlated with post-translational O-Glucosamine-N-Acetylation (O-GlcNAcylation) and ubiquitination of A20, targeting it for proteasomal degradation. Restoring A20 levels by inhibiting O-GlcNAcylation, blocking proteasome activity, or overexpressing A20, blocked upregulation of the receptor for advanced glycation end-products (RAGE) and phosphorylation of PKCβII, two prime atherogenic signals triggered by high glucose in EC/SMC. A20 gene transfer to the aortic arch of diabetic ApoE null mice that develop accelerated atherosclerosis, attenuated vascular expression of RAGE and phospho-PKCβII, significantly reducing atherosclerosis. Conclusions: High glucose/hyperglycemia regulate vascular A20 expression via O-GlcNAcylation-dependent ubiquitination and proteasomal degradation. This could be key to the pathogenesis of accelerated atherosclerosis in diabetes.
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    Foot Muscle Energy Reserves in Diabetic Patients Without and With Clinical Peripheral Neuropathy
    (American Diabetes Association, 2009) Doupis, John; Kuchibhotla, Sarada; Julliard, Walker; Gnardellis, Charalambos; Dinh, Thanh; Lyons, Thomas Edward; Rosenblum, Barry; Wang, Xiaoen; Giurini, John; Greenman, Robert L.; Veves, Aristidis
    Objective: To investigate changes in the foot muscle energy reserves in diabetic non-neuropathic and neuropathic patients. Research Design and Methods: We measured the phosphocreatinine (PCr)/inorganic phosphate (Pi) ratio, total \(^{31}\)P concentration, and the lipid/water ratio in the muscles in the metatarsal head region using MRI spectroscopy in healthy control subjects and non-neuropathic and neuropathic diabetic patients. Results: The PCr/Pi ratio was higher in the control subjects (3.23 \(\pm\) 0.43) followed by the non-neuropathic group (2.61 \(\pm\) 0.36), whereas it was lowest in the neuropathic group (0.60 \(\pm\) 1.02) (P < 0.0001). There were no differences in total \(^{31}\)P concentration and lipid/water ratio between the control and non-neuropathic groups, but both measurements were different in the neuropathic group (P < 0.0001). Conclusions: Resting foot muscle energy reserves are affected before the development of peripheral diabetic neuropathy and are associated with the endothelial dysfunction and inflammation.