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Sitting decreases endothelial microparticles but not circulating angiogenic cells irrespective of lower leg exercises: a randomized cross-over trial.
Evans, WS, Hanson, ED, Shill, DD, Landers-Ramos, RQ, Stoner, L, Willey, Q, Credeur, DP, Prior, SJ
Experimental physiology. 2020;(8):1408-1419
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Abstract
NEW FINDINGS What is the central question of this study? What are the cellular and molecular determinants of increased risk for cardiovascular disease from prolonged sitting? What is the main finding and its importance? Prolonged sitting, independent of calf raise interruption strategies, decreases microparticle counts linked to endothelial activation and apoptosis. An acute bout of prolonged sitting appears to promote paradoxical decreases in microparticle counts, but the implications are not yet clear. ABSTRACT Repeated exposure to prolonged sitting increases the risk for cardiovascular disease. However, the cellular links by which repeated exposure to prolonged sitting lead to increased cardiovascular risk have not been fully elucidated, with markers of vascular damage and repair such as microparticles (MPs) and circulating angiogenic cell (CACs) being promising targets. The objective of the study was to examine the effects of 3 h of sitting with or without intermittent calf raises on annexin V+ /CD34+ , annexin V+ /CD62E+ , and annexin V+ /CD31+ /42b- MP populations linked to CAC paracrine activity, endothelial activation and apoptosis, respectively, as well as CD14+ /31+ , CD3+ /31+ , and CD34+ CACs, which are linked to endothelial repair. In a random order, 20 sedentary participants (14 females, 22 ± 3 years) remained seated for 180 min with or without performing 10 calf raises every 10 min. Blood samples were obtained after 20 min of quiet rest in the supine position before and after sitting. Overall, sitting decreased annexin V+ /CD34+ MPs (-12 ± 5 events µl-1 , P < 0.01), annexin V+ /CD62E+ MPs (-17 ± 4 events µl-1 , P < 0.001), and annexin V+ /CD31+ /42b- MPs (-22 ± 6 events µl-1 , P < 0.001) regardless of condition. There were no differences in endothelin-1 plasma concentration, CD14+ /31+ , CD34+ or CD3+ /31+ CAC frequencies. Sitting did not alter CAC number, but decreased MPs linked to endothelial activation, apoptosis and CAC paracrine activity in a manner that was independent of muscle contraction. These findings support changes in markers of endothelial activation and apoptosis with sedentary behaviour and provide new insights into altered intercellular communication with physical inactivity such as prolonged sitting.
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Evaluation of the Effect Derived from Silybin with Vitamin D and Vitamin E Administration on Clinical, Metabolic, Endothelial Dysfunction, Oxidative Stress Parameters, and Serological Worsening Markers in Nonalcoholic Fatty Liver Disease Patients.
Federico, A, Dallio, M, Masarone, M, Gravina, AG, Di Sarno, R, Tuccillo, C, Cossiga, V, Lama, S, Stiuso, P, Morisco, F, et al
Oxidative medicine and cellular longevity. 2019;:8742075
Abstract
Nowadays, the nonalcoholic fatty liver disease represents the main chronic liver disease in the Western countries, and the correct medical therapy remains a big question for the scientific community. The aim of our study was to evaluate the effect derived from the administration for six months of silybin with vitamin D and vitamin E (RealSIL 100D®) on metabolic markers, oxidative stress, endothelial dysfunction, and worsening of disease markers in nonalcoholic fatty liver disease patients. We enrolled 90 consecutive patients with histological diagnosis of nonalcoholic fatty liver disease and 60 patients with diagnosis of reflux disease (not in therapy) as healthy controls. The nonalcoholic fatty liver disease patients were randomized into two groups: treated (60 patients) and not treated (30 patients). We performed a nutritional assessment and evaluated clinical parameters, routine home tests, the homeostatic model assessment of insulin resistance, NAFLD fibrosis score and fibrosis-4, transient elastography and controlled attenuation parameter, thiobarbituric acid reactive substances, tumor necrosis factor α, transforming growth factor β, interleukin-18 and interleukin-22, matrix metalloproteinase 2, epidermal growth factor receptor, insulin growth factor-II, cluster of differentiation-44, high mobility group box-1, and Endocan. Compared to the healthy controls, the nonalcoholic fatty liver disease patients had statistically significant differences for almost all parameters evaluated at baseline (p < 0.05). Six months after the baseline, the proportion of nonalcoholic fatty liver disease patients treated that underwent a statistically significant improvement in metabolic markers, oxidative stress, endothelial dysfunction, and worsening of disease was greater than not treated nonalcoholic fatty liver disease patients (p < 0.05). Even more relevant results were obtained for the same parameters by analyzing patients with a concomitant diagnosis of metabolic syndrome (p < 0.001). The benefit that derives from the use of RealSIL 100D could derive from the action on more systems able to advance the pathology above all in that subset of patients suffering from concomitant metabolic syndrome.
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Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial.
Tanaka, A, Shimabukuro, M, Okada, Y, Taguchi, I, Yamaoka-Tojo, M, Tomiyama, H, Teragawa, H, Sugiyama, S, Yoshida, H, Sato, Y, et al
Cardiovascular diabetology. 2017;(1):48
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is characterized by systemic metabolic abnormalities and the development of micro- and macrovascular complications, resulting in a shortened life expectancy. A recent cardiovascular (CV) safety trial, the EMPA-REG OUTCOME trial, showed that empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, markedly reduced CV death and all-cause mortality and hospitalization for heart failure in patients with T2DM and established CV disease (CVD). SGLT2 inhibitors are known to not only decrease plasma glucose levels, but also favorably modulate a wide range of metabolic and hemodynamic disorders related to CV pathways. Although some experimental studies revealed a beneficial effect of SGLT2 inhibitors on atherosclerosis, there is a paucity of clinical data showing that they can slow the progression of atherosclerosis in patients with T2DM. Therefore, the EMBLEM trial was designed to investigate whether empagliflozin treatment can improve endothelial function, which plays a pivotal role in the pathogenesis of atherosclerosis, in patients with T2DM and established CVD. METHODS The EMBLEM trial is an ongoing, prospective, multicenter, placebo-controlled double-blind randomized, investigator-initiated clinical trial in Japan. A total of 110 participants with T2DM (HbA1c range 6.0-10.0%) and with established CVD will be randomized (1:1) to receive either empagliflozin 10 mg once daily or a placebo. The primary endpoint of the trial is change in the reactive hyperemia (RH)-peripheral arterial tonometry-derived RH index at 24 weeks from baseline. For comparison of treatment effects between the treatment groups, the baseline-adjusted means and their 95% confidence intervals will be estimated by analysis of covariance adjusted for the following allocation factors: HbA1c (<7.0 or ≥7.0%), age (<65 or ≥65 years), systolic blood pressure (<140 or ≥140 mmHg), and current smoking status (nonsmoker or smoker). Key secondary endpoints include the change from baseline for other vascular-related markers such as arterial stiffness, sympathetic nervous activity, and parameters of cardiac and renal function. Importantly, serious adverse effects independently on the causal relationship to the trial drugs and protocol will be also evaluated throughout the trial period. DISCUSSION EMBLEM is the first trial to assess the effect of empagliflozin on endothelial function in patients with T2DM and established CVD. Additionally, mechanisms associating empagliflozin-mediated actions with endothelial function and other CV markers will be evaluated. Thus, the trial is designed to elucidate potential mechanisms by which empagliflozin protects CV systems and improves CV outcomes. Trial registration Unique Trial Number, UMIN000024502 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028197 ).
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One-year daily consumption of buttermilk drink containing lutein-enriched egg-yolks does not affect endothelial function in fasting and postprandial state.
van der Made, SM, Berendschot, TTJM, Kijlstra, A, Plat, J
Scientific reports. 2017;(1):1353
Abstract
Previous results have shown that one-year daily consumption of a lutein-enriched egg yolk containing dairy drink did not significantly affect fasting serum lipid and lipoprotein concentrations in adults with early signs of macular degeneration. The current study further substantiates these findings with parameters reflecting endothelial function. Additionally, we extend our observations from the fasting to the postprandial situation. Subjects participated in a 1-y randomized placebo-controlled dietary intervention trial. 52 subjects were included in the active (Egg) group and 49 in the control (Con) group. Changes in postprandial biochemistry (triacylglycerol (TAG), glucose and non-esterified fatty acids (NEFA)) following a mixed meal and flow-mediated dilation (FMD) analyses were evaluated at the start and after one year intervention. Postprandial glycemic and lipemic responses before the intervention as well as the differences in postprandial responses after one-year intervention were comparable between the Egg and the Con group. Fasting FMD was comparable between the groups before the intervention started and at the end of intervention. Additionally, the change in FMD following a mixed meal was comparable between the groups. To conclude, one-year consumption of a lutein-enriched egg yolk incorporated in a dairy drink has no effect on postprandial lipid and glucose metabolism or endothelial function.
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Repeated supra-maximal sprint cycling with and without sodium bicarbonate supplementation induces endothelial microparticle release.
Kirk, RJ, Peart, DJ, Madden, LA, Vince, RV
European journal of sport science. 2014;(4):345-52
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Abstract
Under normal homeostatic conditions, the endothelium releases microparticles (MPs), which are known to increase under stressful conditions and in disease states. CD105 (endoglin) and CD106 (vascular cell adhesion molecule-1) are expressed on the surface of endothelial cells and increased expression in response to stress may be observed. A randomised-controlled double-blinded study aimed to examine the use of endothelial MPs as a marker for the state of one's endothelium, as well as whether maintaining acid-base homeostasis affects the release of these MPs. This study tested seven healthy male volunteers, who completed a strenuous cycling protocol, with venous blood analysed for CD105+ and CD106+ MPs by flow cytometry at regular intervals. Prior to each trial participants consumed either 0.3 g·kg(-1) body mass of sodium bicarbonate (NaHCO3), or 0.045 g·kg(-1) body mass of sodium chloride (NaCl). A significant rise in endothelial CD105+ MPs and CD106+ MPs (p<0.05) was observed at 90 min post-exercise. A significant trend was shown for these MPs to return to resting levels 180 min post-exercise in both groups. No significance was found between experimental groups, suggesting that maintaining acid-base variables closer to basal levels has little effect upon the endothelial stress response for this particular exercise mode. In conclusion, strenuous exercise is accompanied by MP release and the endothelium is able to rapidly recover in healthy individuals, whilst maintaining acid-base homeostasis does not attenuate the MP release from the endothelium after exercise.
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A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease.
Kutlar, A, Ataga, KI, McMahon, L, Howard, J, Galacteros, F, Hagar, W, Vichinsky, E, Cheung, AT, Matsui, N, Embury, SH
American journal of hematology. 2012;(5):536-9
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Abstract
Abnormal blood flow accounts for most of the clinical morbidity of sickle cell disease (SCD) [1,2]. Most notably, occlusion of flow in the microvasculature causes the acute pain crises [3] that are the commonest cause for patients with SCD to seek medical attention [4] and major determinants of their quality of life [5]. Based on evidence that endothelial P-selectin is central to the abnormal blood flow in SCD we provide results from four of our studies that are germane to microvascular blood flow in SCD. A proof-of-principle study established that doses of heparin lower than what are used for anticoagulation but sufficient to block P-selectin improved microvascular blood flow inpatients with SCD. An in vitro study showed that Pentosan Polysulfate Sodium (PPS) had greater P-selectin blocking activity than heparin. A Phase I clinical study demonstrated that a single oral dose of PPS increased microvascular blood flow in patients with SCD. A Phase II clinical study that was not completed documented that daily oral doses of PPS administered for 8 weeks lowered plasma levels of sVCAM-1 and tended to improve microvascular blood flow in patients with SCD. These data support the concept that P-selectin on the microvascular endothelium is critical to both acute vascular occlusion and chronically impaired microvascular blood flow in SCD. They also demonstrate that oral PPS is beneficial to microvascular sickle cell blood flow and has potential as an efficacious agent for long-term prophylactic therapy of SCD.
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Exchanging saturated fatty acids for (n-6) polyunsaturated fatty acids in a mixed meal may decrease postprandial lipemia and markers of inflammation and endothelial activity in overweight men.
Masson, CJ, Mensink, RP
The Journal of nutrition. 2011;(5):816-21
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Abstract
Postprandial lipemia, low-grade systemic inflammation, and endothelial activity are related to metabolic disorders. It is well known that dietary fatty acid composition modulates postprandial lipemia, but information on the other metabolic risk markers is limited. We therefore studied the acute effects of a meal rich in SFA compared with those of a meal rich in (n-6) PUFA on postprandial responses in overweight men who are at an increased risk to develop the metabolic syndrome and its comorbidities. In a crossover design, the effects of 50 g butter (rich in SFA) on lipemia and markers for inflammation and endothelial activity were compared with those of 50 g sunflower oil [rich in (n-6) PUFA] during an 8-h postprandial mixed meal tolerance test in 13 overweight men. Postprandial changes in serum TG were comparable between the meals (P = 0.38), except for a reduction in the incremental area under the curve (P = 0.046) in the late postprandial phase after (n-6) PUFA (125 ± 96 mmol⋅min⋅L(-1)) compared with SFA (148 ± 98 mmol⋅min⋅L(-1)). Compared with the SFA meal, the (n-6) PUFA meal decreased plasma IL-6 (P = 0.003), TNFα (P = 0.005), soluble TNF receptors I and II (sTNFr; P = 0.024 and P < 0.001, respectively), and soluble vascular cell adhesion molecule-1 (sVCAM-1; P = 0.030) concentrations. These results indicate that exchanging SFA from butterfat for (n-6) PUFA in a mixed meal may decrease postprandial lipemia and concentrations of IL-6, TNFα, sTNFr-I and -II, and sVCAM-1 in overweight men.