Abstract 15: Glucose-Mediated Remodeling of Cardiac DNA Methylation

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Mark E Pepin ◽  
David K Crossman ◽  
Joseph P Barchue ◽  
Salpy V Pamboukian ◽  
Steven M Pogwizd ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Dna Methylation ◽  
Diabetic Cardiomyopathy ◽  
Left Ventricular ◽  
Epigenetic Mark ◽  
Gene Transcript ◽  
Transcript Levels ◽  
Glycemic Memory

To identify the role of glucose in the development of diabetic cardiomyopathy, we had directly assessed glucose delivery to the intact heart on alterations of DNA methylation and gene expression using both an inducible heart-specific transgene (glucose transporter 4; mG4H) and streptozotocin-induced diabetes (STZ) mouse models. We aimed to determine whether long-lasting diabetic complications arise from prior transient exposure to hyperglycemia via a process termed “glycemic memory.” We had identified DNA methylation changes associated with significant gene expression regulation. Comparing our results from STZ, mG4H, and the modifications which persist following transgene silencing, we now provide evidence for cardiac DNA methylation as a persistent epigenetic mark contributing to glycemic memory. To begin to determine which changes contribute to human heart failure, we measured both RNA transcript levels and whole-genome DNA methylation in heart failure biopsy samples (n = 12) from male patients collected at left ventricular assist device placement using RNA-sequencing and Methylation450 assay, respectively. We hypothesized that epigenetic changes such as DNA methylation distinguish between heart failure etiologies. Our findings demonstrated that type 2 diabetic heart failure patients (n = 6) had an overall signature of hypomethylation, whereas patients listed as ischemic (n = 5) had a distinct hypermethylation signature for regulated transcripts. The focus of this initial analysis was on promoter-associated CpG islands with inverse changes in gene transcript levels, from which diabetes (14 genes; e.g. IGFBP4) and ischemic (12 genes; e.g. PFKFB3) specific targets emerged with significant regulation of both measures. By combining our mouse and human molecular analyses, we provide evidence that diabetes mellitus governs direct regulation of cellular function by DNA methylation and the corresponding gene expression in diabetic mouse and human hearts. Importantly, many of the changes seen in either mouse type 1 diabetes or human type 2 diabetes were similar supporting a consistent mechanism of regulation. These studies are some of the first steps at defining mechanisms of epigenetic regulation in diabetic cardiomyopathy.

scholarly journals Transcriptional and Free Radical Responses to LVAD Therapy

2020 ◽  
Author(s):  
Kajari Dhar ◽  
KC Asmini ◽  
Fang Qiu ◽  
Hesham Basma ◽  
Krupak Savalia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Dna Methylation ◽  
Free Radicals ◽  
Free Radical ◽  
Pathway Analysis ◽  
Dna Methyltransferase ◽  
Left Ventricular ◽  
Differentially Expressed ◽  
Z Score

Abstract Background: Myocardial recovery with Left ventricular assistant device (LVAD) therapy is dichotomous with some patients obtaining remission from end-stage heart failure whereas most require transplantation or remain on pump support long term. Our goal was to determine transcriptional and free radical responses to LVAD treatment. Methods: Tissues were collected from patients before and after LVAD placement in non-ischemic dilated cardiomyopathy patients (n=14) along with controls (n=3). RNA sequencing (RNASeq) analysis quantified transcriptional profiles by using a custom targeted panel of heart failure related genes on the PGM sequencer. The differential expression analysis between groups was conducted using edgeR (Empirical analysis of digital gene expression data in R) package in Bioconductor. Ingenuity Pathway Analysis (IPA) was carried out on differentially expressed genes to understand the biological pathways involved. Electron Paramagnetic Resonance (EPR) Spectroscopy was utilized to measure levels of free radicals in whole blood collected pre- and post-LVAD implantation (n=16). Results: 35 genes were differentially expressed in pre-LVAD failing hearts compared to controls. In response to LVAD therapy, only Pyruvate dehydrogenase kinase 4 (PDK4) and period circadian protein homolog 1 (PER1) were altered with 34 heart failure related genes still differentially expressed post-LVAD compared to controls. IPA showed that DNA methylation-related genes were upregulated in both pre- and post-LVAD and was persistent with a Z-score of 2.00 and 2.36 for DNA Methyltransferase 3A (DNMT3A) and DNA methyltransferase 3B (DNMT3B), respectively. Inhibition of micro RNA21 (mir21) was also significant on pathway analysis in the post-LVAD population with a Z-score of -2.00. Levels of free radicals in blood of pre- and post-LVAD patients did not change significantly. Conclusion: LVAD therapy does not reverse many of the transcriptional changes associated with heart failure. Persistent changes in gene expression may be related to ongoing oxidative stress, continued DNA methylation, or changes in metabolism. PDK4 is a key regulator of glucose metabolism and its increased expression by LVAD therapy inhibited pyruvate metabolism.

scholarly journals Transcriptional and Free Radical Responses to LVAD Therapy

2020 ◽  
Author(s):  
Kajari Dhar ◽  
KC Asmini ◽  
Fang Qiu ◽  
Hesham Basma ◽  
Krupak Savalia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Dna Methylation ◽  
Free Radicals ◽  
Free Radical ◽  
Pathway Analysis ◽  
Dna Methyltransferase ◽  
Left Ventricular ◽  
Differentially Expressed ◽  
Z Score

Abstract Background: Myocardial recovery with Left ventricular assistant device (LVAD) therapy is dichotomous with some patients obtaining remission from end-stage heart failure whereas most require transplantation or remain as destination therapy. Our goal was to determine transcriptional and free radical responses to LVAD treatment. Methods: Tissues were collected from patients before and after LVAD placement in non-ischemic dilated cardiomyopathy patients (n=14) along with non-failing controls (n=3). RNA sequencing (RNASeq) analysis quantified transcriptional profiles by using a custom targeted panel of heart failure related genes on the PGM sequencer. The differential expression analysis between groups was conducted using edgeR (Empirical analysis of digital gene expression data in R) package in Bioconductor. Ingenuity Pathway Analysis (IPA) was carried out on differentially expressed genes to understand the biological pathways involved. Electron Paramagnetic Resonance (EPR) Spectroscopy was utilized to measure levels of free radicals in whole blood collected pre- and post-LVAD implantation (n=16). Results: 35 genes were differentially expressed in pre-LVAD failing hearts compared to non-failing controls. In response to LVAD therapy, only Pyruvate dehydrogenase kinase 4 (PDK4) and period circadian protein homolog 1 (PER1) were altered with 34 heart failure related genes still differentially expressed post-LVAD compared to non-failing hearts. IPA showed that DNA methylation-related genes were upregulated in both pre- and post-LVAD and was persistent with a Z-score of 2.00 and 2.36 for DNA Methyltransferase 3A (DNMT3A) and DNA methyltransferase 3B (DNMT3B), respectively. Inhibition of micro RNA21 (mir21) was also significant on pathway analysis in the post-LVAD population with a Z-score of -2.00. Levels of free radicals in blood of pre- and post-LVAD patients did not change significantly. Conclusion: LVAD therapy does not reverse many of the transcriptional changes associated with heart failure. Persistent changes in gene expression may be related to ongoing oxidative stress, continued DNA methylation, or changes in metabolism. PDK4 is a key regulator of glucose metabolism and its increased expression by LVAD therapy inhibited pyruvate metabolism.

scholarly journals High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes

Diabetologia ◽  
2012 ◽  
Vol 55 (8) ◽  
pp. 2154-2162 ◽  
Author(s):  
L. J. M. Boonman-de Winter ◽  
F. H. Rutten ◽  
M. J. M. Cramer ◽  
M. J. Landman ◽  
A. H. Liem ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Left Ventricular Dysfunction ◽  
Ventricular Dysfunction ◽  
Left Ventricular ◽  
High Prevalence

Role of angiotensin-signalling in anthracycline-induced cardiotoxicity

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Findlay ◽  
J.H Gill ◽  
R Plummer ◽  
C.J Plummer
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Angiotensin Ii ◽  
Late Onset ◽  
Left Ventricular Systolic Dysfunction ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Funding Source ◽  
Study Results

Abstract   Anthracycline chemotherapy remains a key component of cancer treatment regimens in both paediatric and adult patients. A significant issue with their use is the development of anthracycline-induced cardiotoxicity (AIC), with subclinical AIC and clinical heart failure observed in 13.8% and 3.1% of patients, respectively. The major clinical complication of AIC is the development of late-onset cardiotoxicity, occurring several years after drug administration, presenting as life-threatening heart failure (HF). Determining the relationship between subclinical AIC and late-onset HF, strategies for mitigation of AIC, and impacts upon the cancer survivor population remains a complex challenge. Administration of drugs targeting the angiotensin system, specifically angiotensin converting enzyme inhibitors (ACEi), have been reported to reduce AIC in the clinic. Whilst the therapeutic effect of ACEi in management of left ventricular systolic dysfunction and consequent HF is principally through optimisation of cardiac haemodynamics, the mechanism involved with mitigation of late-onset AIC several years after anthracycline exposure are currently unknown. Using a variety of human cardiomyocyte in vitro models we have previously demonstrated induction of cardiomyocyte hypertrophy by angiotensin II and anthracyclines. Importantly, selective blockade of the angiotensin II receptor 1 (ATR1) on cardiomyocytes mitigated the anthracycline-induced hypertrophic response, implicating synergism between AIC and angiotensin signalling in cardiomyocytes. Adult human ventricular cardiac myocyte AC10 cell-line were treated in vitro with a range of clinically relevant doxorubicin doses for clinically appropriate durations, with AT1 receptor gene expression evaluated using semi-quantitative PCR. Our results confirm a positive correlation between clinically-relevant concentration of doxorubicin and induction of genetic expression of ATR1 in AC10 cells, with up to 200% increases in ATR1 expression observed. Maximal doxorubicin-induced gene expression being observed at 8 and 24-hours, respectively. These preliminary results agreeing with clinical exposure parameters for this drug with protein expression studies being optimised to support these gene expression study results. Our preliminary studies also imply patients developing AIC carry a deleted polymorphism within intron 16 of the ACE gene and increased systemic levels of the ACE product angiotensin II, both with a known association to hypertrophic cardiomyopathy. Taken together, these data support our mechanistic hypothesis that a relationship exists between AIC and modulation of the angiotensin signalling pathway in cardiomyocytes, involving structural cellular changes and asymptomatic cardiac hypertrophy. An elevation in angiotensin II levels, potentially through polymorphisms in ACE, could thereby exacerbate anthracycline-induced hypertrophy and promote the development of late-onset anthracycline-induced HF. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Cancer Research UK funded PhD

Long-term levosimendan treatment improves systolic function and myocardial relaxation in mice with cardiomyocyte-specific disruption of the Serca2 gene

2013 ◽  
Vol 115 (10) ◽  
pp. 1572-1580 ◽  
Author(s):  
Vigdis Hillestad ◽  
Frank Kramer ◽  
Stefan Golz ◽  
Andreas Knorr ◽  
Kristin B. Andersson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cardiac Function ◽  
Diastolic Dysfunction ◽  
Systolic Function ◽  
Cytosolic Calcium ◽  
Left Ventricular ◽  
Pressure Measurements ◽  
Human Heart Failure

In human heart failure (HF), reduced cardiac function has, at least partly, been ascribed to altered calcium homeostasis in cardiomyocytes. The effects of the calcium sensitizer levosimendan on diastolic dysfunction caused by reduced removal of calcium from cytosol in early diastole are not well known. In this study, we investigated the effect of long-term levosimendan treatment in a murine model of HF where the sarco(endo)plasmatic reticulum ATPase ( Serca) gene is specifically disrupted in the cardiomyocytes, leading to reduced removal of cytosolic calcium. After induction of Serca2 gene disruption, these mice develop marked diastolic dysfunction as well as impaired contractility. SERCA2 knockout (SERCA2KO) mice were treated with levosimendan or vehicle from the time of KO induction. At the 7-wk end point, cardiac function was assessed by echocardiography and pressure measurements. Vehicle-treated SERCA2KO mice showed significantly diminished left-ventricular (LV) contractility, as shown by decreased ejection fraction, stroke volume, and cardiac output. LV pressure measurements revealed a marked increase in the time constant (τ) of isovolumetric pressure decay, showing impaired relaxation. Levosimendan treatment significantly improved all three systolic parameters. Moreover, a significant reduction in τ toward normalization indicated improved relaxation. Gene-expression analysis, however, revealed an increase in genes related to production of the ECM in animals treated with levosimendan. In conclusion, long-term levosimendan treatment improves both contractility and relaxation in a heart-failure model with marked diastolic dysfunction due to reduced calcium transients. However, altered gene expression related to fibrosis was observed.

Abstract 16485: The Nitroxyl Donor 1-Nitrosocyclohexyl Acetate Limits Cardiac Superoxide Upregulation and Diastolic Dysfunction in a Mouse Model of Diabetic Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Rebecca H Ritchie ◽  
Nga Cao ◽  
Yung George Wong ◽  
Sarah Rosli ◽  
Helen Kiriazis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Ex Vivo ◽  
Systolic Function ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Diastolic Dysfunction ◽  
The Impact

Nitroxyl (HNO), a redox congener of NO•, is a novel regulator of cardiovascular function combining vasodilator and positive inotropic properties. Our previous studies have demonstrated these properties occur concomitantly in the intact heart; HNO moreover also exhibits antihypertrophic and superoxide-suppressing actions. HNO donors may thus offer favorable actions in heart failure. The impact of chronic HNO donor administration has however yet to be reported in this context. We tested the hypothesis that the HNO donor 1-nitrosocyclohexyl acetate (1-NCA) limits cardiomyocyte hypertrophy and left ventricular (LV) diastolic dysfunction in a mouse model of diabetic cardiomyopathy in vivo. Male 6 week-old FVB/N mice received either streptozotocin (55 mg/kg/day i.p. for 5 days, n=17), to induce type 1 diabetes, or citrate vehicle (n=16). After 4 weeks of hyperglycemia, mice were allocated to 1-NCA therapy (83mg/kg/day i.p.) or vehicle, and followed for a further 4 weeks. As shown in the table, blood glucose was unaffected by 1-NCA. LV diastolic dysfunction was evident in diabetic mice, measured as echocardiography-derived A wave velocity, deceleration time and E:A ratio; LV systolic function was preserved. Diabetes-induced diastolic dysfunction was accompanied by increased LV cardiomyocyte size, hypertrophic and pro-fibrotic gene expression, and upregulation of LV superoxide. These characteristics of diabetic cardiomyopathy were largely prevented by 1-NCA treatment. Selectivity of 1-NCA as a donor of HNO versus NO• was demonstrated by the sensitivity of the coronary vasodilation response of 1-NCA to the HNO scavenger L-cysteine (4mM), but not to the NO• scavenger hydroxocobalamin (50μM), in the normal rat heart ex vivo (n=3-7). Collectively, our studies provide the first evidence that HNO donors may represent a promising new strategy for the treatment of diabetic cardiomyopathy, and implies their therapeutic efficacy in settings of chronic heart failure.

Abstract 370: Type 2 Diabetes Is Associated with the Exacerbation of Heart Failure via Increasing Myocardial NAD(P)H Oxidase-Derived Superoxide Production

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shintaro Kinugawa ◽  
Shouji Matsushima ◽  
Takashi Yokota ◽  
Yukihiro Ohta ◽  
Naoki Inoue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Diastolic Pressure ◽  
Interstitial Fibrosis ◽  
Left Ventricular ◽  
Lung Weight ◽  
Tissue Mass ◽  
Tibial Length ◽  
Lv Remodeling

Type 2 diabetes mellitus (DM) adversely affects the outcomes in patients with myocardial infarction (MI), which is associated with the development of left ventricular (LV) remodeling and failure. NAD(P)H oxidase-derived superoxide (O 2 − ) production is increased in DM. However, its pathophysiological significance in advanced post-MI LV failure associated with DM remains unestablished. We thus determined whether an inhibitor of NAD(P)H oxidase activation, apocynin, could attenuate the exacerbated LV remodeling and heart failure after MI in high-fat diet (HFD)-induced obese mice with DM. Male C57BL/6J mice were fed on either HFD or normal diet (ND) for 8 weeks. At 4 weeks of feeding, MI was created in all mice by ligating left coronary artery. MI mice were treated with either apocynin (10 mmol/l in drinking water; n = 10 for ND and n = 11 for HFD) or vehicle (n = 15 for ND and n = 13 for HFD). HFD significantly increased body weight (BW), adipose tissue mass, fasting plasma glucose and insulin levels compared to ND after 4 and 8 weeks. HFD + MI had significantly greater LV end-diastolic diameter (LVEDD; 5.7 ± 0.1 vs. 5.3 ± 0.2 mm) by echocardiography, end-diastolic pressure (EDP; 12 ± 2 vs. 8 ± 1 mmHg) and lung weight/tibial length (10.1 ± 0.3 vs. 8.7 ± 0.7 mg/mm) than ND + MI, which was accompanied by an increased interstitial fibrosis of non-infarcted LV. Treatment of HFD + MI with apocynin significantly decreased LVEDD (5.4 ± 0.1 mm), LVEDP (9.7 ± 0.8 mmHg), lung weight/tibial length (9.0 ± 0.3 mg/mm), and concomitantly interstitial fibrosis of non-infarcted LV to ND + MI level without affecting BW, glucose metabolism, infarct size and aortic pressure. On the other hand, treatment of ND + MI with apocynin did not affect LV remodeling and failure. NAD(P)H oxidase activity, O 2 − production measured by lucigenin chemiluminescence, and thiobarbituric acid-reactive substances were increased in non-infarcted LV tissues from HFD + MI, all of which were also attenuated by apocynin to ND + MI level. Type 2 DM was associated with the exacerbation of LV remodeling and failure after MI via increasing NAD(P)H oxidase derived O 2 − production, which may be a novel important therapeutic target in advanced heart failure with DM.

Клиническое значение результатов исследования DAPA HF (Dapagliflozin and prevention of adverse-outcomes in heart failure) для пациентов и врачей. Консенсус совета Экспертов

2021 ◽  
Vol 1 (223) ◽  
pp. 2-14
Author(s):  
Gulmira Alipova ◽  
◽  
Anna Bazarova ◽  
Nazira Bazarova ◽  
Rimma Bazarbekova ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Ejection Fraction ◽  
Cardiovascular Death ◽  
Left Ventricular ◽  
Adverse Outcomes ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Persistent Symptoms

The article presents the results of the DAPA-HF study - evaluating the efficacy of dapagliflozin, used at a dose of 10 mg once a day, in addition to the standard treatment for patients with chronic heart failure with reduced left ventricular ejection fraction, compared to placebo. An analysis of current clinical recommendations related to this issue was carried out, the results of recent clinical studies and metaanalyses conducted were highlighted. Based on the results of the study, the need is postulated to optimize drug therapy of this category to patients with persistent symptoms of heart failure, despite standard therapy, with the addition of dapagliflozin to reduce the risk of cardiovascular death and hospitalizations for heart failure, improve the course of the disease. Keywords: chronic heart failure, dapagliflozin, low ejection fraction, effects of type 2 sodium-glucose co transporter inhibitors, diabetes mellitus.

scholarly journals Limitations of transcriptome-based prediction of pathogenicity genes in the plant pathogen Leptosphaeria maculans

2019 ◽  
Vol 366 (7) ◽  
Author(s):  
Andrew S Urquhart ◽  
Alexander Idnurm
Keyword(s):  
Gene Expression ◽  
Brassica Napus ◽  
Leptosphaeria Maculans ◽  
Simple Expression ◽  
Gene Transcript ◽  
Blackleg Disease ◽  
Fungal Pathogenicity ◽  
Transcript Levels ◽  
Oilseed Crops ◽  
High Gene

ABSTRACT Identification of pathogenicity determinants in Leptosphaeria maculans, a major cause of disease of oilseed crops, has been a focus of research for many years. A wealth of gene expression information from RNA sequencing promises to illuminate the mechanisms by which the fungus is able to cause blackleg disease. However, to date, no studies have tested the hypothesis that high gene transcript levels during infection correlate with importance to disease progression. In this study, we use CRISPR-Cas9 to disrupt 11 genes that are highly expressed during the early stages of disease and show that none of these genes are crucial for fungal pathogenicity on Brassica napus. This finding suggests that in order to understand the pathogenicity of this fungus more sophisticated techniques than simple expression analysis will need to be employed.

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