scholarly journals Διερεύνηση του ρόλου του πυρηνικού υποδοχέα PPARβ στην καρδιά φυσιολογικών και διαβητικών επίμυων

2014 ◽  
Author(s):  
Ελευθερία Γαλάτου
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
Fatty Acids ◽  
Glucose Metabolism ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Expression Levels ◽  
Diabetic Myocardium

Cardiovascular diseases are one of the major causes of morbidity and mortality in the modern world. They are characterized by molecular, cellular and pathophysiological changes in the myocardium, a condition known as cardiac remodeling. While short-term cardiac remodeling is an adaptive response that contributes to the maintenance of cardiac function the long term remodeling leads to contractile dysfunction and eventually heart failure while it is also associated with sudden death from arrhythmias. The energy metabolism of the heart and the utilization of various substrates are modified in various pathological conditions, including cardiac hypertrophy, which is associated with an increase in the catabolism of glucose and reduction of the oxidation of fatty acids, while diabetes mellitus is characterized by increased by enhanced fatty acid metabolism and reduced glucose and lactate metabolism. Given that peroxisome proliferator activated receptors (PPARs) are key transcriptional regulators of energy metabolism and lipid homeostasis, the aim of this thesis was to investigate the role of PPARα/δ activation in cardiac hypertrophy, diabetes mellitus and ischaemia.Primary cultures of cardiomyocytes were exposed to the specific PPARα/δ agonist, GW0742, and then they were treated with a1 adrenergic agonist, phenylephrine (PE). GW0742 inhibited PE- induced increase in cell area and expression of ANP and BNP. The inhibitory effect of GW0742 on cell growth and gene expression was abolished in the presence of GSK0660, a PPARα/δ antagonist. Furthermore, gene expression levels of PPARα/δ and the target genes of the receptor involved in the oxidation of fatty acids (mCPT-1, UCP3) and glucose metabolism (PDK4, GLUT4) were determined. PE- induced down- regulation of PPARα/δ and target genes, was reversed in the presence of GW0742. These results show that activation of PPARα/δ probably compensates for the metabolic dysfunction that characterizes cardiac hypertrophy, by adjusting fatty acids oxidation and glucose metabolism.The molecular mechanisms that contribute to the development of cardiac hypertrophy include, among others, kinase signaling pathways, (MAPK, PI3K/Akt), and reactive oxygen species (ROS). GW0742 inhibited PE -induced ROS production modulating signaling and redox mechanisms that are involved in cardiac hypertrophy. The non genomic role of GW0742 was confirmed by using the antagonist GSK0660. Furthermore, a second aim was to evaluate whether the administration of GW0742, improves cardiac dysfunction in diabetes and to explore the underlying molecular mechanisms of cardioprotection. For this purpose we used the experimental model of streptozotocin (65mg/kg) induced diabetes in rats with total duration of six weeks. GW0742 was found to reduce glucose, cholesterol and triglyceride levels in blood plasma, improve impairment of cardiac contractility, decrease the diabetes-induced fibrosis and inhibits hypertrophy. Additionally, in order to assess the changes in myocardial metabolism both in streptozotocin-induced diabetes and after administration of GW0742, we determined gene expression of PPARα/δ and of the target genes involved in glucose metabolism (GLUT4) and fatty acids (MCAD and mCPT-1). The results showed that PPARα/δ, MCAD and mCPT-1 expression increased in the diabetic myocardium and remained elevated in the presence of GW0742 but at lower levels. Furthermore, GW0742 administration in diabetic animals restored the decreased expression levels of GLUT4 in the control group. These results suggest that glucose metabolism could be compensated in these animals. In parallel, we investigated whether autophagy mechanisms are involved in this experimental model of diabetes mellitus and assessed the effect of GW0742 on them. For this purpose, expression levels of autophagy marker proteins LC3II, p62 and Beclin-1 were determined. We showed that autophagy levels were reduced by diabetes, but were restored to basal levels in the presence of GW0742. Finally, it was determined the infarct size and the effect of GW0742 on ischemia-induced ventricular arrhythmias and on physiological pressure parameters (LVDP) in normal and diabetic animals. The results indicate that GW0742 and WY14643 reduce infarct size and arrhythmias in both normal and diabetic model, via activation of transcription factors PPARα/δ and PPARα, respectively. Furthermore, expression of PPARα/δ and target gene GLUT4 was determined. GLUT4 expression levels are reduced after ischemia/ reperfusion (I/R) in both normal and diabetic myocardium, which is reversed in the presence of GW0742. In contrast, administration of WY14643 in normal animals restores expression of GLUT4 after I/ R. These results suggest that PPARα ηαζ PPARα/δ regulate the expression of GLUT4 differently, although the latter is a target gene of both.

scholarly journals Synergistic effects of ivabradine and metformin in the treatment of concomitant chronic heart failure and diabetes mellitus by regulating the activity of the H19/miR-423-5p/HCN4 axis

2021 ◽  
Author(s):  
Fang Zhang ◽  
Weijun Jiang ◽  
Yating Liu ◽  
Liu Li ◽  
Rui Wang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Chronic Heart Failure ◽  
Real Time ◽  
Therapeutic Effect ◽  
Real Time Pcr ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Synergistic Effects

IntroductionIn this study, the molecular mechanisms underlying the therapeutic effect of metformin (MET) and ivabradine (IBD) in the treatment of concomitant chronic heart failure (CHF) and diabetes mellitus (DM) were investigated.Material and methodsBasic and cardiac indexes were measured to study the therapeutic effect of MET and IBD. Real-time PCR, IHC assays, in-silicon analysis, luciferase assays, real-time PCR and Western blot assays were conducted to clarify the molecular mechanisms underlying the interaction between MET and IBD.ResultsMET administration restored the normal values of general/cardiac indexes in CHF rats. The abnormal values of echocardiographic indexes in CHF rats with STZ-induced DM were all corrected by a certain degree after the MET administration. Moreover, the injection of STZ up-regulated the expression of plasma NE/BNP-45, while the IBD administration reduced the levels of NE/BNP-45 in CHF rats. Furthermore, the administration of MET also reduced the NE level in CHF rats, indicating that both MET and IBD can exert a therapeutic effect on CHF rats. Additionally, in-silicon analysis and luciferase assays verified the role of H19 and HCN4 as target genes of miR-423-5p. In fact, the transfection of MET or H19 siRNA1/2 into HL-1 and H9C2 cells down-regulated the levels of H19 and HCN4 while increasing the level of miR-423-5p.ConclusionsMET reduces H19 expression via inducing methylation of its promoter, and the inhibited H19 expression suppresses HCN4 expression by up-regulating miR-423-5p expression. As a result, the suppressed expression of HCN4 reduces heart rate and exhibits a therapeutic effect in the treatment of concomitant CHF and DM.

scholarly journals The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury

2020 ◽  
Vol 31 (4) ◽  
pp. 716-730 ◽  
Author(s):  
Marc Johnsen ◽  
Torsten Kubacki ◽  
Assa Yeroslaviz ◽  
Martin Richard Späth ◽  
Jannis Mörsdorf ◽  
...  
Keyword(s):  
Gene Expression ◽  
Reperfusion Injury ◽  
Caloric Restriction ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypoxic Preconditioning ◽  
Preventive Strategies ◽  
Gene Expression Signatures

BackgroundAlthough AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized that these preconditioning strategies use similar pathways to augment cellular stress resistance.MethodsTo identify genes and pathways shared by caloric restriction and hypoxic preconditioning, we used RNA-sequencing transcriptome profiling to compare the transcriptional response with both modes of preconditioning in mice before and after renal ischemia-reperfusion injury.ResultsThe gene expression signatures induced by both preconditioning strategies involve distinct common genes and pathways that overlap significantly with the transcriptional changes observed after ischemia-reperfusion injury. These changes primarily affect oxidation-reduction processes and have a major effect on mitochondrial processes. We found that 16 of the genes differentially regulated by both modes of preconditioning were strongly correlated with clinical outcome; most of these genes had not previously been directly linked to AKI.ConclusionsThis comparative analysis of the gene expression signatures in preconditioning strategies shows overlapping patterns in caloric restriction and hypoxic preconditioning, pointing toward common molecular mechanisms. Our analysis identified a limited set of target genes not previously known to be associated with AKI; further study of their potential to provide the basis for novel preventive strategies is warranted. To allow for optimal interactive usability of the data by the kidney research community, we provide an online interface for user-defined interrogation of the gene expression datasets (http://shiny.cecad.uni-koeln.de:3838/IRaP/).

scholarly journals The role of m6A modification in the biological functions and diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiulin Jiang ◽  
Baiyang Liu ◽  
Zhi Nie ◽  
Lincan Duan ◽  
Qiuxia Xiong ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Rna Modification ◽  
Biological Functions ◽  
Rna Methylation ◽  
Downstream Target ◽  
Different Types ◽  
M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

scholarly journals The Role of Translation Initiation Regulation in Haematopoiesis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Godfrey Grech ◽  
Marieke von Lindern
Keyword(s):  
Gene Expression ◽  
Translation Initiation ◽  
Translational Control ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Regulation Of Gene Expression ◽  
Mrna Translation ◽  
Translation Control ◽  
Haematological Disorders

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control.

scholarly journals Discovery of MicroRNAs and Their Target Genes Related to Drought in Paulownia “Yuza 1” by High-Throughput Sequencing

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Minjie Deng ◽  
Yabing Cao ◽  
Zhenli Zhao ◽  
Lu Yang ◽  
Yanfang Zhang ◽  
...  
Keyword(s):  
Drought Stress ◽  
Molecular Mechanisms ◽  
High Throughput Sequencing ◽  
Plant Hormone ◽  
Target Genes ◽  
Reference Data ◽  
Relevant Information ◽  
Putative Target

Understanding the role of miRNAs in regulating the molecular mechanisms responsive to drought stress was studied in Paulownia “yuza 1.” Two small RNA libraries and two degradome libraries were, respectively, constructed and sequenced in order to detect miRNAs and their target genes associated with drought stress. A total of 107 miRNAs and 42 putative target genes were identified in this study. Among them, 77 miRNAs were differentially expressed between drought-treated Paulownia “yuza 1” and the control (60 downregulated and 17 upregulated). The predicted target genes were annotated using the GO, KEGG, and Nr databases. According to the functional classification of the target genes, Paulownia “yuza 1” may respond to drought stress via plant hormone signal transduction, photosynthesis, and osmotic adjustment. Furthermore, the expression levels of seven miRNAs (ptf-miR157b, ptf-miR159b, ptf-miR398a, ptf-miR9726a, ptf-M2153, ptf-M2218, and ptf-M24a) and their corresponding target genes were validated by quantitative real-time PCR. The results provide relevant information for understanding the molecular mechanism of Paulownia resistance to drought and reference data for researching drought resistance of other trees.

Abstract 314: BRaf Plays a Major Role in Gene Expression in Cardiomyocytes in Mouse Hearts in vivo

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Michelle A Hardyman ◽  
Stephen J Fuller ◽  
Daniel N Meijles ◽  
Kerry A Rostron ◽  
Sam J Leonard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Braf Mutations ◽  
Gene Markers ◽  
Lv Mass ◽  
Cardiac Volumes

Introduction: Raf kinases lie upstream of ERK1/2 with BRaf being the most highly expressed and having the highest basal activity. V600E BRaf mutations constitutively activate ERK1/2 and are common in cancer. The role of BRaf in the adult heart is yet to be established. ERK1/2 regulate cardiomyocyte gene expression, promoting cardiac hypertrophy and cardioprotection, but effects of ERK1/2 may depend on signal strength. Hypothesis: Our hypotheses are that BRaf is critical in regulating ERK1/2 signaling in cardiomyocytes and, whilst moderate ERK1/2 activity is beneficial, excessive ERK1/2 activity is detrimental to the heart. Methods: We generated heterozygote mice for tamoxifen- (Tam-) inducible cardiomyocyte-specific knockin of V600E in the endogenous BRaf gene. Mice (12 wks) received 2 injections of Tam or vehicle on consecutive days (n=4-10 per group). Kinase activities and mRNA expression were assessed by immunoblotting and qPCR. Echocardiography was performed (Vevo2100). M-mode images (short axis view) were analyzed; data for each mouse were normalized to the mean of 2 baseline controls. Results: V600E knockin did not affect overall BRaf or cRaf levels in mouse hearts, but significantly increased ERK1/2 activities within 48 h (1.51±0.05 fold). Concurrently, mRNAs for hypertrophic gene markers including BNP and immediate early genes (IEGs) increased signficantly. At 72 h, expression of BNP, Fosl1, Myc, Ereg and CTGF increased further, other IEGs (Jun, Fos, Egr1, Atf3) declined, and ANF was upregulated. In contrast, expression of α and β myosin heavy chain mRNAs was substantially downregulated (0.46/0.41±0.05 relative to controls). Within 72 h, left ventricular (LV) mass and diastolic LV wall thickness had increased (1.23±0.05 relative to controls), but cardiac function was severely compromised with significant decreases in ejection fraction and cardiac output (0.53/0.68±0.09 relative to controls) associated with increased LV internal diameters and cardiac volumes. Conclusions: Endogenous cardiomyocyte BRaf is sufficient to activate ERK1/2 in mouse hearts and induce cardiac hypertrophy associated with dynamic temporal changes in gene expression. However, excessive activation of ERK1/2 in isolation is detrimental to cardiac function.

Abstract P460: Role Of Hopx In Antiretroviral Drugs Induced Cardiac Hypertrophy And Epigenetic Modification

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Shiridhar Kashyap ◽  
Olena Kondrachuk ◽  
Manish K Gupta
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Epigenetic Modification ◽  
Trichostatin A ◽  
Antiretroviral Drugs ◽  
Functional Enrichment ◽  
Hiv Patients ◽  
Acetylation Level

Background: Heart failure is the one of the leading causes of death in HIV patients. Application ofantiretroviral therapy (ART) raise the life expectancy of HIV patients, but survival population show higherrisk of cardiovascular disorder. The aim of this study is to understand the underlying molecular mechanismof antiretroviral drugs (ARVs) induced cardiac dysfunction in HIV patients. Method and Results: To determine the mechanism of ARVs induced cardiac dysfunction, we performeda global transcriptomic profiling in primary cardiomyocytes treated with ARVs. Differentially expressedgenes were identified by DESeq2. Functional enrichment analysis of differentially expressed genes wereperformed using clusterProfiler R and ingenuity pathway analysis. Our data show that ARVs treatmentcauses upregulation of several biological function associated with cardiotoxicity and heart failure.Interestingly, we found that ARV drugs treatment significantly upregulates the expression of a set of genesinvolved cardiac enlargement and hypertrophy in the heart. Global gene expression data were validated inthe cardiac tissue isolated from the HIV patients having history of ART treatment. Interestingly, we foundthat the homeodomain-containing only protein homeobox (HOPX) expression was significantly increasedin transcriptional and translational level in cardiomyocytes treated with ARV drugs as well as in heart tissueof ART treated HIV patients. Further, we performed adenovirus mediated gain in and siRNA mediatedknockdown approach to determine the role of HOPX in ARVs mediated cardiac hypertrophy and epigeneticmodifications. Mechanistically, we found that HOPX expression level plays a key role in ARV drugsmediated increased cardiomyocytes cell size and reduced acetylation level of histone 3 at lysine 9 and lysine27. Furthermore, we found that knockdown of HOPX gene expression blunted the hypertrophy effect ofARV drugs in cardiomyocytes. It is known that HOPX reduces cellular acetylation level through interactionwith HDAC2. In our study, we found that histone deacetylase inhibitor Trichostatin A can restore cellularacetylation level in presence of ARVs. Conclusion: ART treatment causes cardiotoxicity through regulation of fatal gene expression incardiomyocytes and in adult heart. Additionally, we found that HOPX expression is critical in ARVsmediated cardiomyocytes remodeling and epigenetic modification.

scholarly journals Distinct effects of oleic acid and itstrans-isomer elaidic acid on the expression of myokines and adipokines in cell models

2011 ◽  
Vol 105 (8) ◽  
pp. 1226-1234 ◽  
Author(s):  
Nuria Granados ◽  
Jaume Amengual ◽  
Joan Ribot ◽  
Andreu Palou ◽  
M. Luisa Bonet
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Oleic Acid ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Elaidic Acid ◽  
C2c12 Myotubes ◽  
Cell Models ◽  
Monounsaturated Fat ◽  
Expression Levels

Trans-fatty acids (TFA) andcis-monounsaturated fat appear to exert detrimental and beneficial effects, respectively, on glucose metabolism and insulin sensitivity. Adipose tissue and skeletal muscle are a source of signalling proteins (adipokines and myokines), some of which have been related to the control of insulin sensitivity. Here, we investigated the possible differential effects of elaidic acid (EA;trans-9-18 : 1) – the major component in industrially produced TFA – and oleic acid (OA;cis-9-18 : 1) – itscis-isomer naturally present in food – on cellular glucose uptake and the expression of selected myokines and adipokines using cell models. Differentiated C2C12 myotubes and 3T3-L1 adipocytes were pretreated with the vehicle (control cells) or fatty acids for 24 h, after which basal and insulin-stimulated 2-deoxyglucose uptake and the expression of selected signalling proteins were measured. In C2C12 myotubes, pretreatment with OA, but not with EA, led to increased insulin-stimulated 2-deoxyglucose uptake and IL-6 expression levels, while pretreatment with EA, but not with OA, led to reduced IL-15 mRNA levels and increased TNF-α expression levels. In 3T3-L1 adipocytes, exposure to OA, but not to EA, resulted in reduced resistin gene expression and increased adiponectin gene expression. The results show evidence of distinct, direct effects of OA and EA on muscle glucose uptake and the expression of target myokines and adipokines, thus suggesting novel mechanisms by whichcis- andtrans-monounsaturated fat may differentially affect systemic functions.

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