| 1. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 2. |
- Lundby, A. K. M., et al.
(författare)
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Kidney-synthesized erythropoietin is the main source for the hypoxia-induced increase in plasma erythropoietin in adult humans
- 2014
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Ingår i: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6319 .- 1439-6327. ; 114:6, s. 1107-1111
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Tidskriftsartikel (refereegranskat)abstract
- Erythropoietin (EPO) is mainly synthesized within renal peritubular fibroblasts, and also other tissues such as the liver possess the ability. However, to what extent non-kidney produced EPO contributes to the hypoxia-induced increase in circulating EPO in adult humans remains unclear. We aimed to quantify this by assessing the distribution of EPO glycoforms which are characterized by posttranslational glycosylation patterns specific to the synthesizing cell. The analysis was performed on samples obtained in seven healthy volunteers before, during and after 1 month of sojourn at 3,454 m altitude. Umbilical cord (UC) plasma served as control. As expected a peak (p < 0.05) in urine (2.3 +/- A 0.5-fold) and plasma (3.3 +/- A 0.5-fold) EPO was observed on day 1 of high-altitude exposure, and thereafter the concentration decreased for the urine sample obtained after 26 days at altitude, but remained elevated (p < 0.05) by 1.5 +/- A 0.2-fold above the initial sea level value for the plasma sample. The EPO glycoform heterogeneity, in the urine samples collected at altitude, did not differ from values at sea level, but were markedly lower (p < 0.05) than the mean percent migrated isoform (PMI) for the umbilical cord samples. Our studies demonstrate (1) UC samples express a different glycoform distribution as compared to adult humans and hence illustrates the ability to synthesis EPO in non-kidney cells during fetal development (2) as expected hypoxia augments circulating EPO in adults and the predominant source here for remains being kidney derived.
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| 3. |
- Bonne, T. C., et al.
(författare)
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Phlebotomy eliminates the maximal cardiac output response to six weeks of exercise training
- 2014
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Ingår i: American Journal of Physiology-Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 306:10
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Tidskriftsartikel (refereegranskat)abstract
- With this study we tested the hypothesis that 6 wk of endurance training increases maximal cardiac output (Q(max)) relatively more by elevating blood volume (BV) than by inducing structural and functional changes within the heart. Nine healthy but untrained volunteers (Vo(2max) 47 +/- 5 ml.min(-1).kg(-1)) underwent supervised training (60 min; 4 times weekly at 65% Vo(2max) for 6 wk), and Q(max) was determined by inert gas rebreathing during cycle ergometer exercise before and after the training period. After the training period, blood volume (determined in duplicates by CO rebreathing) was reestablished to pretraining values by phlebotomy and Q(max) was quantified again. Resting echography revealed no structural heart adaptations as a consequence of the training intervention. After the training period, plasma volume (PV), red blood cell volume (RBCV), and BV increased (P < 0.05) by 147 +/- 168 (5 +/- 5%), 235 +/- 64 (10 +/- 3%), and 382 +/- 204 ml (7 +/- 4%), respectively. Vo(2max) was augmented (P < 0.05) by 10 +/- 7% after the training period and decreased (P < 0.05) by 8 +/- 7% with phlebotomy. Concomitantly, Q(max) was increased (P < 0.05) from 18.9 +/- 2.1 to 20.4 +/- 2.3 l/min (9 +/- 6%) as a consequence of the training intervention, and after normalization of BV by phlebotomy Q(max) returned to pretraining values (18.1 +/- 2.5 l/min; 12 +/- 5% reversal). Thus the exercise training-induced increase in BV is the main mechanism increasing Q(max) after 6 wk of endurance training in previously untrained subjects.
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| 4. |
- Calbet, J.A.L., et al.
(författare)
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Chronic hypoxia increases arterial blood pressure and reduces adenosine and ATP induced vasodilatation in skeletal muscle in healthy humans
- 2014
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 211:4, s. 574-584
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To determine the role played by adenosine, ATP and chemoreflex activation on the regulation of vascular conductance in chronic hypoxia. Methods: The vascular conductance response to low and high doses of adenosine and ATP was assessed in ten healthy men. Vasodilators were infused into the femoral artery at sea level and then after 8-12 days of residence at 4559 m above sea level. At sea level, the infusions were carried out while the subjects breathed room air, acute hypoxia (FIO2 = 0.11) and hyperoxia (FIO2 = 1); and at altitude (FIO2 = 0.21 and 1). Skeletal muscle P2Y2 receptor protein expression was determined in muscle biopsies after 4 weeks at 3454 m by Western blot. Results: At altitude, mean arterial blood pressure was 13% higher (91 ± 2 vs. 102 ± 3 mmHg, P < 0.05) than at sea level and was unaltered by hyperoxic breathing. Baseline leg vascular conductance was 25% lower at altitude than at sea level (P < 0.05). At altitude, the high doses of adenosine and ATP reduced mean arterial blood pressure by 9-12%, independently of FIO2. The change in vascular conductance in response to ATP was lower at altitude than at sea level by 24 and 38%, during the low and high ATP doses respectively (P < 0.05), and by 22% during the infusion with high adenosine doses. Hyperoxic breathing did not modify the response to vasodilators at sea level or at altitude. P2Y2 receptor expression remained unchanged with altitude residence. Conclusions: Short-term residence at altitude increases arterial blood pressure and reduces the vasodilatory responses to adenosine and ATP. © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.
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| 5. |
- Sun, Jianmin, et al.
(författare)
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The PI3-kinase isoform p110 delta is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner
- 2014
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 33:46, s. 5360-5369
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Tidskriftsartikel (refereegranskat)abstract
- PI3-kinase has a crucial role in transformation mediated by the oncogenic c-Kit mutant D816V. In this study, we demonstrate that the c-Kit/D816V-mediated cell survival is dependent on an intact direct binding of PI3-kinase to c-Kit. However, mutation of this binding site had little effect on the PI3-kinase activity in the cells, suggesting that c-Kit/D816V-mediated cell survival is dependent on PI3-kinase but not its kinase activity. Furthermore, inhibition of the lipid kinase activity of PI3-kinase led only to a slight inhibition of cell survival. Knockdown of the predominant PI3-kinase isoform p110 delta in c-Kit/D816V-expressing Ba/F3 cells led to reduced cell transformation both in vitro and in vivo without affecting the overall PI3-kinase activity. This suggests that p110 delta has a lipid-kinaseindependent role in c-Kit/D816V-mediated cell transformation. We furthermore demonstrate that p110 delta is phosphorylated at residues Y524 and S1039 and that phosphorylation requires an intact binding site for PI3-kinase in c-Kit/D816V. Overexpression of p110 delta carrying the Y523F and S1038A mutations significantly reduced c-Kit/D816V-mediated cell survival and proliferation. Taken together, our results demonstrate an important lipid-kinase-independent role of p110 delta in c-Kit/D816V-mediated cell transformation. This furthermore suggests that p110 delta could be a potential diagnostic factor and selective therapeutic target for c-Kit/D816V-expressing malignancies.
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