scholarly journals Prolonged administration of a dithiol antioxidant protects against ventricular remodeling due to ischemia-reperfusion in mice

2008 ◽  
Vol 295 (3) ◽  
pp. H1303-H1310 ◽  
Author(s):  
S. Kelly Ambler ◽  
Yvonne K. Hodges ◽  
Gayle M. Jones ◽  
Carlin S. Long ◽  
Lawrence D. Horwitz
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Ventricular Remodeling ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Ribonuclease Protection Assay ◽  
Pathological Cardiac Hypertrophy ◽  
Echocardiographic Measurement ◽  
Abnormal Pattern ◽  
Ribonuclease Protection

The prolonged production of reactive oxygen species due to ischemia-reperfusion (I/R) is a potential cause of the pathological remodeling that frequently precedes heart failure. We tested the ability of a potent dithiol antioxidant, bucillamine, to protect against the long-term consequences of I/R injury in a murine model of myocardial infarction. After transiently occluding the left anterior descending coronary artery for 30 min, saline or bucillamine (10 μg/g body wt) was injected intravenously as a bolus within the first 5 min of reperfusion. The antioxidant treatment continued with daily subcutaneous injections for 4 wk. There were no differences in infarct sizes between bucillamine- and saline-treated animals. After 4 wk of reperfusion, cardiac hypertrophy was decreased by bucillamine treatment (ventricular weight-to-body weight ratios: I/R + saline, 4.5 ± 0.2 mg/g vs. I/R + bucillamine, 4.2 ± 0.1 mg/g; means ± SE; P < 0.05). Additionally, the hearts of bucillamine-treated mice had improved contractile function (echocardiographic measurement of fractional shortening) relative to saline controls: I/R + saline, 32 ± 3%, versus I/R + bucillamine, 41 ± 4% ( P < 0.05). Finally, I/R-induced injury in the saline-treated mice was accompanied by a fetal pattern of gene expression determined by ribonuclease protection assay that was consistent with pathological cardiac hypertrophy and remodeling [increased atrial natriuretic peptide, β-myosin heavy chain (MHC), skeletal α-actin; decreased sarco(endo)plasmic reticulum Ca2+ ATPase 2a, and α-MHC-to-β-MHC ratio]. These changes in gene expression were significantly attenuated by bucillamine. Therefore, treatment with a dithiol antioxidant for 4 wk after I/R preserved ventricular function and prevented the abnormal pattern of gene expression associated with pathological cardiac remodeling.

scholarly journals Emodin Attenuates Pathological Cardiac Hypertrophy by Regulating Gene Expression Through Acetyl-histone-mediated Actions (P06-036-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Levi Evans ◽  
Bradley Ferguson
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Histone Acetylation ◽  
Regulation Of Gene Expression ◽  
Epigenetic Modifications ◽  
Neonatal Rat ◽  
Heart Health ◽  
Hdac Activity ◽  
Pathological Cardiac Hypertrophy ◽  
Epigenetic Regulators

Abstract Objectives Epigenetic modifications regulate gene expression without changing DNA sequence and are reversible, highlighting their therapeutic potential for heart failure. Recent evidence suggests that food compounds can reverse these stress-induced epigenetic modifications, yet few studies have characterized their role as epigenetic regulators of heart health. Our objective tested the hypothesis that Emodin, an Antraquinone found in rhubarb, blocked pathological cardiac hypertrophy via acetyl-histone-mediated gene expression changes. Methods To test this hypothesis, neonatal rat ventricular myocytes (NRVMs) were stimulated with phenylephrine (PE, 10 μM) to induce receptor-mediated pathological cardiac hypertrophy in the absence or presence of vehicle control or Emodin (10 μM) for 48 hours. Cells were subsequently 1) fixed for immunostaining and cell size quantification, 2) lysed for protein to assess HDAC activity and histone acetylation or 3) lysed for RNA to analyze transcriptome–wide changes in gene expression. A minimum of three experiments with an n = 3/group was performed and data quantified. One-way ANOVA with Tukey's post-hoc was performed unless otherwise specified. p < 0.05 was considered significant. Results Emodin significantly blocked PE-induced hypertrophy. Emodin significantly inhibited HDAC activity concomitant to increased histone acetylation. Lastly, Emodin reversed stress-induced changes in gene expression. Conclusions Our data suggest that Emodin inhibited pathological cardiac hypertrophy via acetyl-histone dependent regulation of gene expression. While animal studies are currently underway to examine the epigenetic actions for emodin in cardiac protection, our results support the role for food compounds like Emodin as epigenetic regulators of heart health. Funding Sources This work is supported by the USDA NIFA (Hatch-NEV00727), the Dennis Meiss & Janet Ralston Fund for Nutri-epigenetic Research and by the National Institute for General Medical Sciences (NIGMS) of the NIH (P20 GM130459) to B.S.F. Core facilities used for Research were supported by NIGMS of the NIH (P20 GM103554).

Abstract 422: CITED4 is Sufficient to Induce Physiologic Cardiac Hypertrophy and Necessary to Protect Against Pathological Hemodynamic Stress

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Carolin Lerchenmueller ◽  
Vassilios J Bezzeridis ◽  
Colin Platt ◽  
Chunyang Xiao ◽  
Anthony Rosenzweig
Keyword(s):  
Cardiac Hypertrophy ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Mtor Signaling ◽  
Swimming Exercise ◽  
Heart Weight ◽  
Hemodynamic Stress ◽  
Post Surgery ◽  
Adverse Remodeling

Cardiac hypertrophy is an adaptive response to increased physiologic or pathologic hemodynamic stress. Previous work from our laboratory suggested that the CEBPβ/ CITED4 pathway plays an important role in exercise-induced cardiac hypertrophy. Consistent with this model, our laboratory recently found that inducible cardiac expression of CITED4 in adult mice increases heart weight and cardiomyocyte size with normal systolic function and a gene expression profile consistent with physiologic growth. After ischemia-reperfusion injury (IRI), induced CITED4 mice show significant functional recovery and evidence for decreased adverse remodeling. Next, we sought to investigate the role of CITED4 in the setting of physiologic (forced swimming exercise) and pathological (transverse aortic constriction, TAC) cardiac hypertrophy. Cardiomyocyte-specific CITED4 knockout mice (C4KO) undergoing a three week swimming exercise protocol showed modestly but significantly reduced systolic function when compared to control animals (%FS controls 55.4±1.09 vs. C4KO 51.75±0.86; p=0.025). C4KO mice exposed to TAC demonstrated a more rapid and severe decline in cardiac function after TAC (at 6 weeks post surgery, %FS controls 41.55±2.06 vs. C4KO 32.51±2.67; p=0.024). Both in vitro and in vivo we demonstrate that CITED4 is necessary and sufficient for activation of mTOR signaling. Of note, mTORC1 inhibition by rapamycin abrogated the beneficial effects of CITED4 expression after IRI. Taken together, our data identify CITED4 as a novel regulator of mTOR signaling. Moreover they demonstrate that CITED4 is sufficient for physiologic growth and to protect against adverse remodeling after ischemic injury. CITED4 is also necessary for adaptive responses to pathological biomechanical stress and may represent a novel therapeutic target to mitigate adverse ventricular remodeling.

Sp3 inhibits Sp1-mediated activation of the cardiac troponin T promoter and is downregulated during pathological cardiac hypertrophy in vivo

2006 ◽  
Vol 291 (2) ◽  
pp. H600-H611 ◽  
Author(s):  
Anthony Azakie ◽  
Jeffrey R. Fineman ◽  
Youping He
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Cardiac Troponin ◽  
Troponin T ◽  
Cardiac Troponin T ◽  
Pathological Cardiac Hypertrophy ◽  
Cardiac Gene Expression ◽  
Cardiac Gene ◽  
Embryonic Cardiomyocytes

Combinatorial interactions between cis elements and trans-acting factors are required for regulation of cardiac gene expression during normal cardiac development and pathological cardiac hypertrophy. Sp factors bind GC boxes and are implicated in recruitment and assembly of the basal transcriptional complex. In this study, we show that the cardiac troponin T (cTnT) promoter contains a GC box that is necessary for basal and cAMP-mediated activity of cTnT promoter constructs transfected in embryonic cardiomyocytes. Cardiac nuclear proteins bind the cTnT GC box in a sequence-specific fashion and consist of Sp1, Sp2, and Sp3 protein factors. By chromatin immunoprecipitation, Sp1 binds the cTnT promoter “in vivo.” Cotransfected Sp1 trans-activates the cTnT promoter in cardiomyocytes in culture. Sp3 represses Sp1-mediated transcriptional activation of the cTnT gene in embryonic cardiomyocytes. Sp3 repression of Sp1-mediated cTnT promoter activation is dose dependent, inferring a mechanism of competitive binding/inhibition. To evaluate the role of Sp factors in cardiac gene expression in vivo, we have established a clinically relevant animal model of pathological cardiac hypertrophy where the fetal cardiac program is activated. In this animal model, cardiac hypertrophy results from increased left-right shunting, volume loading of the left ventricle, and pressure loading of the right ventricle. Sp1 expression is increased in all four hypertrophied cardiac chambers, whereas Sp3 expression is diminished. This observation is consistent with the in vitro activating function of Sp1 and inhibitory effects of Sp3 on activity of cTnT promoter constructs. Sp factor levels are modulated during the hypertrophic cardiac program in vivo.

Effects of exercise training on pathological cardiac hypertrophy related gene expression and apoptosis

2006 ◽  
Vol 97 (2) ◽  
pp. 216-224 ◽  
Author(s):  
Young I. Lee ◽  
Joon Y. Cho ◽  
Mun H. Kim ◽  
Kee B. Kim ◽  
Dong J. Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Exercise Training ◽  
Cardiac Hypertrophy ◽  
Related Gene ◽  
Pathological Cardiac Hypertrophy

Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure

2005 ◽  
Vol 21 (3) ◽  
pp. 314-323 ◽  
Author(s):  
Henk P. J. Buermans ◽  
Everaldo M. Redout ◽  
Anja E. Schiel ◽  
René J. P. Musters ◽  
Marian Zuidwijk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Contractile Function ◽  
Pyrrolizidine Alkaloid ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Pressure Overload ◽  
High Dose ◽  
Specific Expression

Myocardial right ventricular (RV) hypertrophy due to pulmonary hypertension is aimed at normalizing ventricular wall stress. Depending on the degree of pressure overload, RV hypertrophy may progress to a state of impaired contractile function and heart failure, but this cannot be discerned during the early stages of ventricular remodeling. We tested whether critical differences in gene expression profiles exist between ventricles before the ultimate development of either a compensated or decompensated hypertrophic phenotype. Both phenotypes were selectively induced in Wistar rats by a single subcutaneous injection of either a low or a high dose of the pyrrolizidine alkaloid monocrotaline (MCT). Spotted oligonucleotide microarrays were used to investigate pressure-dependent cardiac gene expression profiles at 2 wk after the MCT injections, between control rats and rats that would ultimately develop either compensated or decompensated hypertrophy. Clustering of significantly regulated genes revealed specific expression profiles for each group, although the degree of hypertrophy was still similar in both. The ventricles destined to progress to failure showed activation of pro-apoptotic pathways, particularly related to mitochondria, whereas the group developing compensated hypertrophy showed blocked pro-death effector signaling via p38-MAPK, through upregulation of MAPK phosphatase-1. In summary, we show that, already at an early time point, pivotal differences in gene expression exist between ventricles that will ultimately develop either a compensated or a decompensated phenotype, depending on the degree of pressure overload. These data reveal genes that may provide markers for the early prediction of clinical outcome as well as potential targets for early intervention.

scholarly journals LbetaT2 gonadotroph cells secrete follicle stimulating hormone (FSH) in response to active A

1999 ◽  
Vol 162 (3) ◽  
pp. R1-R5 ◽  
Author(s):  
KE Graham ◽  
KD Nusser ◽  
MJ Low
Keyword(s):  
Gene Expression ◽  
Luteinizing Hormone ◽  
Cell Line ◽  
Follicle Stimulating Hormone ◽  
Activin A ◽  
Gonadotropin Releasing Hormone ◽  
Ribonuclease Protection Assay ◽  
Protection Assay ◽  
Ribonuclease Protection ◽  
Stimulating Hormone

Secretion of luteinizing hormone in response to gonadotropin releasing hormone (GnRH) has been described in the recently developed LbetaT2 gonadotroph cell line. We evaluated the expression of follicle stimulating hormone (FSH)beta mRNA and secretion of FSH from LbetaT2 cells in response to GnRH and activin A. LbetaT2 cells were treated with activin A in doses from 0 to 50 ng/ml, with or without a daily 10 nM GnRH pulse, or with GnRH alone. FSH secretion was stimulated over 6-fold by concomitant GnRH and activin A in a dose-responsive fashion at 72 h of treatment. FSHbeta mRNA was detectable by ribonuclease protection assay only in cells treated with activin A with or without GnRH. The demonstration of FSHbeta gene expression in LbetaT2 cells further validates these cells as mature, differentiated gonadotrophs and as an important tool for the study of gonadotroph physiology.

scholarly journals A peptide of the N terminus of GRK5 attenuates pressure-overload hypertrophy and heart failure

2021 ◽  
Vol 14 (676) ◽  
pp. eabb5968
Author(s):  
Ryan C. Coleman ◽  
Akito Eguchi ◽  
Melissa Lieu ◽  
Rajika Roy ◽  
Eric W. Barr ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
G Protein ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Pressure Overload ◽  
Nuclear Accumulation ◽  
Nuclear Targeting ◽  
Amino Terminal

Aberrant changes in gene expression underlie the pathogenesis and progression of pressure-overload heart failure, leading to maladaptive cardiac hypertrophy, ventricular remodeling, and contractile dysfunction. Signaling through the G protein Gq triggers maladaptation and heart failure, in part through the activation of G protein–coupled receptor kinase 5 (GRK5). Hypertrophic stimuli induce the accumulation of GRK5 in the nuclei of cardiomyocytes, where it regulates pathological gene expression through multiple transcription factors including NFAT. The nuclear targeting of GRK5 is mediated by an amino-terminal (NT) domain that binds to calmodulin (CaM). Here, we sought to prevent GRK5-mediated pathology in pressure-overload maladaptation and heart failure by expressing in cardiomyocytes a peptide encoding the GRK5 NT (GRK5nt) that encompasses the CaM binding domain. In cultured cardiomyocytes, GRK5nt expression abrogated Gq-coupled receptor–mediated hypertrophy, including attenuation of pathological gene expression and the transcriptional activity of NFAT and NF-κB. We confirmed that GRK5nt bound to and blocked Ca2+-CaM from associating with endogenous GRK5, thereby preventing GRK5 nuclear accumulation after pressure overload. We generated mice that expressed GRKnt in a cardiac-specific fashion (TgGRK5nt mice), which exhibited reduced cardiac hypertrophy, ventricular dysfunction, pulmonary congestion, and cardiac fibrosis after chronic transverse aortic constriction. Together, our data support a role for GRK5nt as an inhibitor of pathological GRK5 signaling that prevents heart failure.

Abstract 301: CITED4 Gene Therapy Alters Maladaptive Cardiac Remodeling After Ischemia-reperfusion Injury

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Carolin Lerchenmüller ◽  
Charles P Rabolli ◽  
Dongjian Hu ◽  
Vassilios J Bezzerides ◽  
Colin Platt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Cardiac Hypertrophy ◽  
Reperfusion Injury ◽  
Cardiac Remodeling ◽  
Ischemia Reperfusion Injury ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Heart Weight ◽  
Adverse Remodeling

Introduction: Cardiac hypertrophy is an adaptive response to increased physiologic or pathologic hemodynamic stress. Previous work from our laboratory suggested that the CEBPβ/ CITED4 pathway plays an important role in exercise-induced cardiac hypertrophy. Consistent with this model, our laboratory recently found that inducible cardiac expression of CITED4 in adult mice increases in heart weight and cardiomyocyte size with normal systolic function and a gene expression profile consistent with physiologic growth. After ischemia-reperfusion injury (IRI), induced CITED4 mice show significant functional recovery and evidence for decreased adverse remodeling. Hypothesis: Here, we assessed the hypothesis that CITED4 gene therapy delivered in a clinically relevant time frame after IRI in a mouse model, will also lead to improved systolic function and favorable cardiac remodeling. Methods and Results: Cardiomyocyte-specific CITED4 gene delivery via intravenous AAV9 (CITED4 and GFP control) injections in young wild type (WT) mice led to a steady 4-fold increase in cardiac CITED4 expression. After four weeks, CITED4 treated animals developed physiologic cardiac hypertrophy with increased heart weights (heart weight to tibia length controls 6.54±0.17g/mm vs. CITED4 7.31±0.12g/mm), as well as increased left ventricular mass index and wall thickness with unchanged systolic function evaluated by echocardiography. CITED4 gene therapy in the setting of IRI, delivered 20min. after reperfusion, promoted decreased maladaptive remodeling with improved systolic function (%FS controls 37.5±3.6 vs. C4KO 47.9±1.6), a smaller scar size (% fibrotic area controls 9.1±1.9 vs. C4KO 2.4±0.5) and a favorable gene expression profile eight weeks after IRI. After injury, CITED4 gene therapy led to a 6-fold overexpression already after one week post-IRI, responsible for less apoptosis, fibrosis and inflammation when compared to control mice. Conclusion: Taken together, our data identify CITED4 as a regulator of physiologic cardiac growth that protects against adverse remodeling after ischemic injury in a clinically relevant therapeutic intervention after IRI. CITED4 may represent a novel therapeutic target to mitigate adverse ventricular remodeling.

Sign in / Sign up

Export Citation Format

Share Document