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Aberrant Phenotype in Human Endothelial Cells of Diabetic Origin: Implications for Saphenous Vein Graft Failure?Roberts, A.C., Gohil, J., Hudson, L., Connolly, K., Warburton, P., Suman, R., O'Toole, P., O'Regan, D.J., Turner, N.A., Riches-Suman, Kirsten, Porter, K.E. 2015 March 1915 (has links)
Yes / Type 2 diabetes (T2DM) confers increased risk of endothelial dysfunction, coronary heart disease, and vulnerability to vein graft failure after bypass grafting, despite glycaemic control. This study explored the concept that endothelial cells (EC) cultured from T2DM and nondiabetic (ND) patients are phenotypically and functionally distinct. Cultured human saphenous vein- (SV-) EC were compared between T2DM and ND patients in parallel. Proliferation, migration, and in vitro angiogenesis assays were performed; western blotting was used to quantify phosphorylation of Akt, ERK, and eNOS. The ability of diabetic stimuli (hyperglycaemia, TNF-α, and palmitate) to modulate angiogenic potential of ND-EC was also explored. T2DM-EC displayed reduced migration (~30%) and angiogenesis (~40%) compared with ND-EC and a modest, nonsignificant trend to reduced proliferation. Significant inhibition of Akt and eNOS, but not ERK phosphorylation, was observed in T2DM cells. Hyperglycaemia did not modify ND-EC function, but TNF-α and palmitate significantly reduced angiogenic capacity (by 27% and 43%, resp.), effects mimicked by Akt inhibition. Aberrancies of EC function may help to explain the increased risk of SV graft failure in T2DM patients. This study highlights the importance of other potentially contributing factors in addition to hyperglycaemia that may inflict injury and long-term dysfunction to the homeostatic capacity of the endothelium.
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Elevated expression levels of microRNA-143/5 in saphenous vein smooth muscle cells from patients with type 2 diabetes drive persistent changes in phenotype and functionRiches-Suman, Kirsten, Alshanwani, A.R., Warburton, P., O'Regan, D.J., Ball, S.G., Wood, I.C., Turner, N.A., Porter, K.E. 09 1900 (has links)
Yes / Type 2 diabetes (T2DM) promotes premature atherosclerosis and inferior prognosis after arterial reconstruction. Vascular smooth muscle cells (SMC) respond to patho/physiological stimuli, switching between quiescent contractile and activated synthetic phenotypes under the control of microRNAs (miRs) that regulate multiple genes critical to SMC plasticity. The importance of miRs to SMC function specifically in T2DM is unknown. This study was performed to evaluate phenotype and function in SMC cultured from non-diabetic and T2DM patients, to explore any aberrancies and investigate underlying mechanisms. Saphenous vein SMC cultured from T2DM patients (T2DM-SMC) exhibited increased spread cell area, disorganised cytoskeleton and impaired proliferation relative to cells from non-diabetic patients (ND-SMC), accompanied by a persistent, selective up-regulation of miR-143 and miR-145. Transfection of premiR-143/145 into ND-SMC induced morphological and functional characteristics similar to native T2DM-SMC; modulating miR-143/145 targets Kruppel-like factor 4, alpha smooth muscle actin and myosin VI. Conversely, transfection of antimiR-143/145 into T2DM-SMC conferred characteristics of the ND phenotype. Exposure of ND-SMC to transforming growth factor beta (TGFβ) induced a diabetes-like phenotype; elevated miR-143/145, increased cell area and reduced proliferation. Furthermore, these effects were dependent on miR-143/145. In conclusion, aberrant expression of miR-143/145 induces a distinct saphenous vein SMC phenotype that may contribute to vascular complications in patients with T2DM, and is potentially amenable to therapeutic manipulation.
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Type 2 diabetes impairs venous, but not arterial smooth muscle cell function: possible role of differential RhoA activityRiches-Suman, Kirsten, Warburton, P., O'Regan, D.J., Turner, N.A., Porter, K.E. 02 March 2014 (has links)
Yes / Background/purpose
Coronary heart disease is the leading cause of morbidity in patients with type 2 diabetes mellitus (T2DM), frequently resulting in a requirement for coronary revascularization using the internal mammary artery (IMA) or saphenous vein (SV). Patency rates of SV grafts are inferior to IMA and further impaired by T2DM whilst IMA patencies appear similar in both populations. Smooth muscle cells (SMC) play a pivotal role in graft integration; we therefore examined the phenotype and proliferative function of IMA- and SV-SMC isolated from non-diabetic (ND) patients or those diagnosed with T2DM.
Methods/materials
SMC were cultured from fragments of SV or IMA. Morphology was analyzed under light microscopy (spread cell area measurements) and confocal microscopy (F-actin staining). Proliferation was analyzed by cell counting. Levels of RhoA mRNA, protein and activity were measured by real-time RT-PCR, western blotting and G-LISA respectively.
Results
IMA-SMC from T2DM and ND patients were indistinguishable in both morphology and function. By comparison, SV-SMC from T2DM patients exhibited significantly larger spread cell areas (1.5-fold increase, P < 0.05), truncated F-actin fibers and reduced proliferation (33% reduction, P < 0.05). Furthermore, lower expression and activity of RhoA were observed in SV-SMC of T2DM patients (37% reduction in expression, P < 0.05 and 43% reduction in activity, P < 0.01).
Conclusions
IMA-SMC appear impervious to phenotypic modulation by T2DM. In contrast, SV-SMC from T2DM patients exhibit phenotypic and functional changes accompanied by reduced RhoA activity. These aberrancies may be epigenetic in nature, compromising SMC plasticity and SV graft adaptation in T2DM patients.
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Mapping the methylation status of the miR-145 promoter in saphenous vein smooth muscle cells from individuals with type 2 diabetesRiches-Suman, Kirsten, Huntriss, J., Keeble, C., Wood, I.C., O'Regan, D.J., Turner, N.A., Porter, K.E. 2016 December 1921 (has links)
Yes / Type 2 diabetes mellitus prevalence is growing globally, and the leading cause of mortality in these patients is cardiovascular
disease. Epigenetic mechanisms such as microRNAs (miRs) and DNA methylation may contribute to complications of
type 2 diabetes mellitus. We discovered an aberrant type 2 diabetes mellitus–smooth muscle cell phenotype driven by
persistent up-regulation of miR-145. This study aimed to determine whether elevated expression was due to changes
in methylation at the miR-145 promoter. Smooth muscle cells were cultured from saphenous veins of 22 non-diabetic
and 22 type 2 diabetes mellitus donors. DNA was extracted, bisulphite treated and pyrosequencing used to interrogate
methylation at 11 CpG sites within the miR-145 promoter. Inter-patient variation was high irrespective of type 2 diabetes
mellitus. Differential methylation trends were apparent between non-diabetic and type 2 diabetes mellitus–smooth
muscle cells at most sites but were not statistically significant. Methylation at CpGs −112 and −106 was consistently
lower than all other sites explored in non-diabetic and type 2 diabetes mellitus–smooth muscle cells. Finally, miR-145
expression per se was not correlated with methylation levels observed at any site. The persistent up-regulation of miR-
145 observed in type 2 diabetes mellitus–smooth muscle cells is not related to methylation at the miR-145 promoter.
Crucially, miR-145 methylation is highly variable between patients, serving as a cautionary note for future studies of this
region in primary human cell types.
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Revascularisation of type 2 diabetics with coronary artery disease: Insights and therapeutic targeting of O-GlcNAcylationBolanle, I.O., Riches-Suman, Kirsten, Loubani, M., Williamson, R., Palmer, T.M. 05 May 2021 (has links)
Yes / Coronary artery bypass graft (CABG) using autologous saphenous vein continues to be a gold standard procedure to restore the supply of oxygen-rich blood to the heart muscles in coronary artery disease (CAD) patients with or without type 2 diabetes mellitus (T2DM). However, CAD patients with T2DM are at higher risk of graft failure. While failure rates have been reduced through improvements in procedure-related factors, much less is known about the molecular and cellular mechanisms by which T2DM initiates vein graft failure. This review gives novel insights into these cellular and molecular mechanisms and identifies potential therapeutic targets for development of new medicines to improve vein graft patency.
One important cellular process that has been implicated in the pathogenesis of T2DM is protein O-GlcNAcylation, a dynamic, reversible post-translational modification of serine and threonine residues on target proteins that is controlled by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Protein O-GlcNAcylation impacts a range of cellular processes, including trafficking, metabolism, inflammation and cytoskeletal organisation. Altered O-GlcNAcylation homeostasis have, therefore, been linked to a range of human pathologies with a metabolic component, including T2DM.
We propose that protein O-GlcNAcylation alters vascular smooth muscle and endothelial cell function through modification of specific protein targets which contribute to the vascular re-modelling responsible for saphenous vein graft failure in T2DM.
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Dermal fibroblasts cultured from donors with type 2 diabetes mellitus retain an epigenetic memory associated with poor wound healing responsesAl-Rikabi, Aaiad H.A., Tobin, Desmond J., Riches-Suman, Kirsten, Thornton, M. Julie 31 March 2021 (has links)
Yes / The prevalence of Type 2 diabetes mellitus (T2DM) is escalating globally. Patients suffer from multiple complications including the development of chronic wounds that can lead to amputation. These wounds are characterised by an inflammatory environment including elevated tumour necrosis factor alpha (TNF-α). Dermal fibroblasts (DF) are critical for effective wound healing, so we sought to establish whether there were any differences in DF cultured from T2DM donors or those without diabetes (ND-DF). ND- and T2DM-DF when cultured similarly in vitro secreted comparable concentrations of TNF-α. Functionally, pre-treatment with TNF-α reduced the proliferation of ND-DF and transiently altered ND-DF morphology; however, T2DM-DF were resistant to these TNF-α induced changes. In contrast, TNF-α inhibited ND- and T2DM-DF migration and matrix metalloprotease expression to the same degree, although T2DM-DF expressed significantly higher levels of tissue inhibitor of metalloproteases (TIMP)-2. Finally, TNF-α significantly increased the secretion of pro-inflammatory cytokines (including CCL2, CXCL1 and SERPINE1) in ND-DF, whilst this effect in T2DM-DF was blunted, presumably due to the tendency to higher baseline pro-inflammatory cytokine expression observed in this cell type. Collectively, these data demonstrate that T2DM-DF exhibit a selective loss of responsiveness to TNF-α, particularly regarding proliferative and secretory functions. This highlights important phenotypic changes in T2DM-DF that may explain the susceptibility to chronic wounds in these patients. / This study was funded by an Iraqi government studentship to AHAA-R.
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Role of microRNA-145 in DNA damage signalling and senescence in vascular smooth muscle cells of Type 2 diabetic patientsHemmings, K.E., Riches-Suman, Kirsten, Bailey, M.A., O'Regan, D.J., Turner, N.A., Porter, K.E. 05 May 2021 (has links)
Yes / Increased cardiovascular morbidity and mortality in individuals with type 2 diabetes (T2DM) is a significant clinical problem. Despite advancements in achieving good glycaemic control,
this patient population remains susceptible to macrovascular complications. We previously discovered that vascular smooth muscle cells (SMC) cultured from T2DM patients exhibit persistent phenotypic aberrancies distinct from those of individuals without a diagnosis of T2DM. Notably, persistently elevated expression levels of microRNA-145 co-exist with characteristics consistent with
aging, DNA damage and senescence. We hypothesised that increased expression of microRNA-145 plays a functional role in DNA damage signalling and subsequent cellular senescence specifically in SMC cultured from the vasculature of T2DM patients. In this study, markers of DNA damage
and senescence were unambiguously and permanently elevated in native T2DM versus non-diabetic (ND)-SMC. Exposure of ND cells to the DNA-damaging agent etoposide inflicted a senescent phenotype, increased expression of apical kinases of the DNA damage pathway and elevated expression levels of microRNA-145. Overexpression of microRNA-145 in ND-SMC revealed evidence of functional
links between them; notably increased secretion of senescence-associated cytokines and chronic activation of stress-activated intracellular signalling pathways, particularly the mitogen-activated protein kinase, p38a. Exposure to conditioned media from microRNA-145 overexpressing cells resulted in chronic p38a signalling in naïve cells, evidencing a paracrine induction and reinforcement of cell senescence. We conclude that targeting of microRNA-145 may provide a route to novel interventions to eliminate DNA-damaged and senescent cells in the vasculature and to this end further detailed studies are warranted.
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Identifying and targeting the molecular signature of smooth muscle cells undergoing early vascular ageingRichces-Suman, Kirsten, Hussain, Alisah 06 May 2022 (has links)
Yes / Early vascular ageing (EVA) is a pathological phenomenon whereby the vascular system ages more quickly than chronological age. This underpins many cardiovascular diseases including the complications of type 2 diabetes, aneurysm formation and hypertension. Smooth muscle cells (SMC) are the principal cell type in the vascular wall and maintain vascular tone. EVA-related phenotypic switching of these cells contributes towards disease progression. EVA is distinct from chronological ageing, and research is ongoing to identify a definitive molecular signature of EVA. This will facilitate the discovery of new clinical tests for early detection of EVA and identify therapeutic targets to halt (or prevent) EVA in SMC, thus reducing macrovascular morbidity and mortality.
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Impact of Diet on the KK-A<sup>y</sup> Mouse Model of Type 2 DiabetesOlivia Nicole Reul (18296653) 03 June 2024 (has links)
<p dir="ltr">Diabetes has become an international health crisis with type 2 diabetes composing the majority of cases. Along with a variety of other systemic effects, type 2 diabetes increases fracture risk. This aspect of type 2 diabetes has become a topic of interest in preclinical research and has been investigated using rodent models of type 2 diabetes. Of these models, the Yellow Kuo Kondo (KK-A<sup>y</sup>) mouse model has shown promise as an obese model of type 2 diabetes. In the KK-A<sup>y</sup> model, mice heterozygous for a mutation in the agouti gene (A<sup>y</sup>) are treated as an obese model of type 2 diabetes. Those that are homozygous (no mutation) are treated as non-diabetic, obese controls. While this model has been indicated to be non-diet dependent, recent data has revealed the efficacy of this model may be reliant on diet. Following approval from the Indiana University-Purdue University at Indianapolis School of Science Institutional Animal Care and Use Committee, mice of each sex and genotype were placed on separate diets. Half on a standard chow diet and the other half on a diet recommended by Jackson Laboratory for this strain. Animals were aged to 16 weeks of age with blood glucose and body weight monitored every other week. Animals were then sacrificed to collect whole blood, blood serum, the pancreas, bilateral tibiae, and bilateral femora. End-point metabolic impacts were assessed through hemoglobin A1c and serum insulin measures while skeletal measures were quantified using microcomputed tomography scanning and analysis. Through this research, it was determined diet did have a significant impact on the skeletal and metabolic phenotype associated with type 2 diabetes in the KK-A<sup>y </sup>model. </p>
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Patienters upplevelse av egenvård vidnydiagnostiserad typ 2 diabetes - en litteraturöversikt / Patients ' experience of self-care in newly diagnosed Type 2 diabetes- a literature reviewAbdullahi, Mahamed Abdiwali, Roopkhomsan, Phimnirin January 2024 (has links)
BakgrundTyp 2 diabetes är en sjukdom som ständigt ökar och leder till många komplikationer. Egenvård är en stor del i behandling, vilket kräver att patienterna har insikten och förmågan till att utföra egenvårdsåtgärderna för att kunna leva med typ 2 diabetes, vilket kan vara utmanande för många patienter. Därför har sjuksköterskan en stor del i behandling av typ 2 diabetes då dessa patienter behöver en hel del undervisning om sjukdomen. SyfteSyftet med studien är att beskriva patienternas upplevelse av egenvård vid nydiagnostiserad typ 2 diabetes. MetodStudien är en litteraturöversikt som besvarar ett syfte med hjälp av vetenskapliga artiklar. Databaserna PubMed och CINAHL användes för att hitta artiklarna. Resultat i denna litteraturöversikt grundades på elva artiklar som publicerades mellan 2014–2024. ResultatStudiens resultat framkom till tre huvudkategorier, sjukdomsacceptens, utmaningar för förändring i levnadsvanor och egenvårdfrämjande faktorer. Sjukdomsacceptansen hade en stor betydelse i hur patienterna engagerade sig i egenvårdsåtgärderna, och utmaningar leder till bristande egenvård. Stöd från hälso-och sjukvården ansågs viktigt hos patienter med typ 2 diabetes. SlutsatsLitteraturstudiens resultat visade att patienterna upplevde att egenvård som nydiagnostiserade typ 2 diabetes var utmanande. Detta på grund av sjukdomen krävde stora insatser från patienterna och kunskap för att kunna leva med sjukdomen. Att bearbeta de känslomässiga reaktioner som tillkommer med sjukdomen hade stort påverkande i hur patienterna följde egenvårdåtgärderna. Stöd var viktigt för patienterna då den främjade patienterna egenvård. / BackgroundType 2 diabetes is a disease that is constantly increasing and leads to many complications. Self-care is a major part of treatment, requiring patients to have the insight and ability to perform the self-care measures in order to live with type 2 diabetes, which can be challenging for many patients. Therefore, the nurse has a great part in the treatment of type 2 diabetes as these patients need a lot of education about the disease. AimTo describe patients ' experience of self-care in newly diagnosed Type 2 diabetes. MethodThe study is a literature review that answers a purpose with the help of scientific articles. The databases PubMed and CINAHL were used to find the articles. Results in this literature review were based on Eleven articles published between 2014–2024. ResultsThe results of the study came to three main categories, disease acceptance, challenges to change in living habits and self-care promoting factors. Disease acceptance had a major impact in how patients engaged in the self-care interventions, and challenges lead to lackof self-care. Health care support was considered important in patients with type 2 diabetes. ConclusionsThe results of the literature study showed that the patients experienced that self-care as newly diagnosed type 2 diabetes was challenging. This because of the disease required great effort from the patients and knowledge in order to be able to live with the disease. Processing the emotional reactions associated with the disease had a major impact on how the patients followed the self-care measures. Support was important for patients as it promoted patient self-care.
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