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Journal articleKalna V, Yang Y, Peghaire C, et al., 2019,
The transcription factor ERG regulates super-enhancers associated with an endothelial-specific gene expression program, Circulation Research, Vol: 124, Pages: 1337-1349, ISSN: 0009-7330
Rationale:The ETS (E-26 transformation-specific) transcription factor ERG (ETS-related gene) is essential for endothelial homeostasis, driving expression of lineage genes and repressing proinflammatory genes. Loss of ERG expression is associated with diseases including atherosclerosis. ERG’s homeostatic function is lineage-specific, because aberrant ERG expression in cancer is oncogenic. The molecular basis for ERG lineage-specific activity is unknown. Transcriptional regulation of lineage specificity is linked to enhancer clusters (super-enhancers).Objective:To investigate whether ERG regulates endothelial-specific gene expression via super-enhancers.Methods and Results:Chromatin immunoprecipitation with high-throughput sequencing in human umbilical vein endothelial cells showed that ERG binds 93% of super-enhancers ranked according to H3K27ac, a mark of active chromatin. These were associated with endothelial genes such as DLL4 (Delta-like protein 4), CLDN5 (claudin-5), VWF (von Willebrand factor), and CDH5 (VE-cadherin). Comparison between human umbilical vein endothelial cell and prostate cancer TMPRSS2 (transmembrane protease, serine-2):ERG fusion-positive human prostate epithelial cancer cell line (VCaP) cells revealed distinctive lineage-specific transcriptome and super-enhancer profiles. At a subset of endothelial super-enhancers (including DLL4 and CLDN5), loss of ERG results in significant reduction in gene expression which correlates with decreased enrichment of H3K27ac and MED (Mediator complex subunit)-1, and reduced recruitment of acetyltransferase p300. At these super-enhancers, co-occupancy of GATA2 (GATA-binding protein 2) and AP-1 (activator protein 1) is significantly lower compared with super-enhancers that remained constant following ERG inhibition. These data suggest distinct mechanisms of super-enhancer regulation in endothelial cells and highlight the unique role of ERG in controlling a core subset of super-enhancers. Most disease-assoc
Journal articleSaxena A, Tiwari P, Wahi N, et al., 2019,
Transcriptome profiling reveals association of peripheral adipose tissue pathology with type-2 diabetes in Asian Indians, Adipocyte, Vol: 8, Pages: 125-136, ISSN: 2162-3945
Type 2 Diabetes (T2D) is a complex disease with an elusive link between its molecular etiology and clinical presentation. Although, the role of visceral adipose tissue in the pathogenesis of insulin resistance and T2D is well known, only a limited information is available on the role of peripheral subcutaneous adipose tissue especiallyin Asian Indians. In this microarray based study of diabetic and normal glucose tolerant (NGT) Asian Indians, we generated the transcription profile of their thigh subcutaneous adipose tissue and further analyzed the diffrentially expressed genes (DEGs) using weighted gene co-expression network analysis (WGCNA) approach. Through WGCNA, we identified the perturbed pathways implicated by these DEGs in relevant co-expression modules by using a topology-based enrichment method. We also attempted to link these pathways with known aspects of T2D pathophysiology in terms of their association with some of their intermediate traits, namely; clinical diagnosis of diabetes, adipocyte size, HOMA-B, and HOMA-R, glycated hemoglobin (Hb1Ac), insulin, glocose level, proinflamatory markers - TNF-α, IL-6, lipid profile markers - Very Low Density Lipids (VLDL), Low Density Lipids (LDL), High Density Lipids (HDL), and Non Esterified Fatty Acids (NEFA). It was observed in this study that several modules of co-expressed genes show an association with diabetes and some of its intermediate phenotypic traits mentioned above. Therefore, these findings suggest a role of peripheral subcutaneous adipose tissue in the pathophsiology of T2D in Asian Indians. Additionally, our study indicated that the peripheral subcutaneous adipose tissue in diabetics shows pathologic changes characterized by adipocyte hypertrophy and upregulation of inflammation related pathways.
Journal articleFord KL, Anwar M, Heys R, et al., 2019,
Optimisation of laboratory methods for whole transcriptomic RNA analyses in human left ventricular biopsies and blood samples of clinical relevance, PLoS ONE, Vol: 14, ISSN: 1932-6203
This study aimed to optimise techniques for whole transcriptome and small RNA analyses on clinical tissue samples from patients with cardiovascular disease. Clinical samples often represent a particular challenge to extracting RNA of sufficient quality for robust RNA sequencing analysis, and due to availability, it is rarely possible to optimise techniques on the samples themselves. Therefore, we have used equivalent samples from pigs undergoing cardiopulmonary bypass surgery to test different protocols for optimal RNA extraction, and then validated the protocols in human samples. Here we present an assessment of the quality and quantity of RNA obtained using a variety of commercially-available RNA extraction kits on both left ventricular biopsies and blood plasma. RNA extraction from these samples presents different difficulties; left ventricular biopsies are small and fibrous, while blood plasma has a low RNA content. We have validated our optimised extraction techniques on human clinical samples collected as part of the ARCADIA (Association of non-coding RNAs with Coronary Artery Disease and type 2 Diabetes) cohort study, resulting in successful whole transcriptome and small RNA sequencing of human left ventricular tissue.
Journal articleShirvani S, Tokarczuk P, Statton B, et al., 2019,
Motion-corrected multiparametric renal arterial spin labelling at 3T: Reproducibility and effect of vasodilator challenge, European Radiology, Vol: 29, Pages: 232-240, ISSN: 0938-7994
ObjectivesWe investigated the feasibility and reproducibility of free-breathing motion-corrected multiple inversion time (multi-TI) pulsed renal arterial spin labelling (PASL), with general kinetic model parametric mapping, to simultaneously quantify renal perfusion (RBF), bolus arrival time (BAT) and tissue T1.MethodsIn a study approved by the Health Research Authority, 12 healthy volunteers (mean age, 27.6 ± 18.5 years; 5 male) gave informed consent for renal imaging at 3 T using multi-TI ASL and conventional single-TI ASL. Glyceryl trinitrate (GTN) was used as a vasodilator challenge in six subjects. Flow-sensitive alternating inversion recovery (FAIR) preparation was used with background suppression and 3D-GRASE (gradient and spin echo) read-out, and images were motion-corrected. Parametric maps of RBF, BAT and T1 were derived for both kidneys. Agreement was assessed using Pearson correlation and Bland-Altman plots.ResultsInter-study correlation of whole-kidney RBF was good for both single-TI (r2 = 0.90), and multi-TI ASL (r2 = 0.92). Single-TI ASL gave a higher estimate of whole-kidney RBF compared to multi-TI ASL (mean bias, 29.3 ml/min/100 g; p <0.001). Using multi-TI ASL, the median T1 of renal cortex was shorter than that of medulla (799.6 ms vs 807.1 ms, p = 0.01), and mean whole-kidney BAT was 269.7 ± 56.5 ms. GTN had an effect on systolic blood pressure (p < 0.05) but the change in RBF was not significant.ConclusionsFree-breathing multi-TI renal ASL is feasible and reproducible at 3 T, providing simultaneous measurement of renal perfusion, haemodynamic parameters and tissue characteristics at baseline and during pharmacological challenge.
Conference paperGuymer SC, Narodden S, Shanmuganathan M, et al., 2018,
Longitudinal Exosomal and Tissue Expression of microRNA-208a and 208b in Acute and Chronic Rat PostMyocardial Infarction Remodelling, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Journal articleMalcor J-D, Juskaite V, Gavriilidou D, et al., 2018,
Coupling of a specific photoreactive triple-helical peptide to crosslinked collagen films restores binding and activation of DDR2 and VWF, Biomaterials, Vol: 182, Pages: 21-34, ISSN: 0142-9612
Collagen-based scaffolds may require chemical crosslinking to achieve mechanical properties suitable for tissue engineering. Carbodiimide treatment, often used for this purpose, consumes amino acid side chains required for receptor recognition, thus reducing cell–collagen interaction. Here, we restore recognition and function of both von Willebrand Factor (VWF) and Discoidin Domain Receptor 2 (DDR2) to crosslinked collagen films by derivatisation with a specific triple-helical peptide (THP), an approach previously applied to integrin-mediated cellular adhesion. The THP contained the collagen III-derived active sequence, GPRGQOGVNleGFO, conjugated to a photoreactive moiety, diazirine, allowing UV-dependent covalent coupling to collagen films. Crosslinking of collagen films attenuated the binding of recombinant VWF A3 domain and of DDR2 (as the GST and Fc fusions, respectively), and coupling of the specific THP restored their attachment. These derivatised films supported activation of DDR2 expressed in either COS-7 or HEK293 cells, reflected by phosphorylation of tyrosine 740, and VWF-mediated platelet deposition from flowing blood was restored. Further, such films were able to increase low-density lipoprotein uptake in vascular endothelial cells, a marker for endothelial phenotype. Thus, covalent linkage of specific THPs to crosslinked collagen films i) restores their cognate protein binding, ii) triggers the corresponding cellular responses, and iii) demonstrates the broad applicability of the approach to a range of receptors for applications in regenerative medicine.
Journal articleEckersley MJ, Sepehripour AH, Casula R, et al., 2018,
Do selective serotonin reuptake inhibitors increase the risk of bleeding or mortality following coronary artery bypass graft surgery? A meta-analysis of observational studies, Perfusion, Vol: 33, Pages: 415-422, ISSN: 1477-111X
INTRODUCTION: Depressive illness has a high prevalence in patients undergoing coronary artery bypass graft surgery (CABG). The first line treatment for depression are selective serotonin reuptake inhibitors (SSRIs) which inhibit serotonin reuptake in the presynaptic neuronal membrane and uptake by platelets, inhibiting subsequent serotonin-mediated platelet activation. This presents a theoretically increased risk of bleeding and subsequent postoperative mortality. This review aims to investigate the effects of SSRIs on postoperative bleeding, defined as the need for transfusions and re-operation for bleeding, as well as 30-day mortality in patients undergoing CABG. METHOD: Four hundred and thirty-seven papers were screened with seven meeting the full inclusion criteria. RESULTS: Meta-analysis demonstrated that SSRI use increased the risk of red blood cell transfusion (odds ratio (OR) = 1.15; 95% confidence interval (CI): 1.06-1.26), but resulted in no difference in the rate of re-operation for bleeding (OR = 1.07; 95% CI: 0.66-1.74). SSRI use had no effect on the rates of platelet (OR = 0.93; 95% CI: 0.79-1.09) or fresh frozen plasma (OR = 0.96; 95% CI: 0.74-1.24) transfusion nor on the mortality rate (OR =1.03; 95 CI: 0.90-1.17). CONCLUSION: This review demonstrates that SSRIs are largely safe in cardiac surgery as no increase in mortality was observed. However, there is a significantly raised chance of red blood cell transfusion. The heterogeneous nature of the current evidence base highlights the need for further research into SSRIs and whether any effect on patient outcomes in cardiac surgery occurs.
Journal articleAlrashed F, Calay D, Lang M, et al., 2018,
Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling, Scientific Reports, Vol: 8, ISSN: 2045-2322
Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs.
Conference paperJuskaite V, Corcoran D, Leitinger B, 2017,
Conference paperBello SO, Singh C, Punjabi P, et al., 2017,
Coronary Reperfusion Ameliorates the Deleterious Effect of Mechanical Unloading on Infarct Size and Interstitial Fibrosis After Acute Myocardial Infarction, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
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