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

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).

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Epigenetic control of exercise training-induced cardiac hypertrophy by miR-208

Clinical Science ◽

10.1042/cs20160480 ◽

2016 ◽

Vol 130 (22) ◽

pp. 2005-2015 ◽

Cited By ~ 29

Author(s):

Ursula Paula Renó Soci ◽

Tiago Fernandes ◽

Valerio Garrone Barauna ◽

Nara Yumi Hashimoto ◽

Gloria de Fátima Alves Mota ◽

...

Keyword(s):

Gene Expression ◽

Exercise Training ◽

Cardiac Hypertrophy ◽

Target Genes ◽

Aerobic Training ◽

Therapeutic Potential ◽

Down Regulation ◽

Epigenetic Control ◽

Cardiac Gene Expression ◽

Cardiac Gene

The physiological training-induced cardiac hypertrophy is epigenetically orchestrated by up-regulation of miR-208a/miR-208b and down-regulation of their target genes: Sox6, Med13, Purβ, SP3 and HP1β. These results highlight the therapeutic potential of aerobic training and miR-208 in cardiac gene expression.

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Effects of angiotensin II and ryanodine on cardiac hypertrophy-related gene expression and calcineurin—NF-AT3 signaling pathway

American Journal of Hypertension ◽

10.1016/s0895-7061(00)01103-1 ◽

2000 ◽

Vol 13 (6) ◽

pp. S309

Author(s):

Z Shanjun

Keyword(s):

Gene Expression ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Signaling Pathway ◽

Related Gene

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01305.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. H600-H611 ◽

Cited By ~ 17

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.

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Abstract 169: Elucidating the role of GRK5 in Physiological Hypertrophy

Circulation Research ◽

10.1161/res.115.suppl_1.169 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Christopher J Traynham ◽

Alessandro Cannavo ◽

Jonathan Hullmann ◽

Jessica L Gold ◽

Walter J Koch

Keyword(s):

Exercise Training ◽

Cardiac Hypertrophy ◽

Cardiac Function ◽

Cardiac Myocyte ◽

Ventricular Myocytes ◽

Neonatal Rat ◽

Heart Weight ◽

Hypertrophic Response ◽

Pathological Cardiac Hypertrophy ◽

Physiological Hypertrophy

Cardiac function is dynamically regulated by various G protein-coupled receptors (GPCRs). GPCR kinases (GRKs) are important in cardiac GPCR regulation through phosphorylation and desensitization of these receptors. GRK2 and GRK5 are the predominant GRKs in the heart, and the most widely characterized as they are both up-regulated in the failing heart. Prior studies from our Lab have determined that GRK5 plays a crucial role in pathological cardiac hypertrophy. Another type of hypertrophy termed, “physiological hypertrophy” occurs with exercise training and is defined as an enlargement in cardiac myocyte size leading to favorable cardiac adaptations. At present, it is unclear if GRK5 is a regulator of physiological hypertrophy in addition to its role in maladaptive hypertrophy. We hypothesize that GRK5 will not regulate physiological hypertrophy such that mice with cardiac-specific overexpression of GRK5 (TgGRK5) will yield a similar post-exercise cardiac physiological hypertrophic response as that of control wild-type (WT) mice. To test this hypothesis, TgGRK5 and WT mice were exposed to a 21 day high-intensity swimming exercise protocol. For each line, sham mice, which did not swim served as appropriate controls. At the conclusion of this protocol, mice were sacrificed and heart weight (HW), body weight (BW), and tibia length (TL) measured. TgGRK5 and WT mice both exhibited a characteristic 10-15% increase in HW/BW and HW/TL ratios, which are standard measures of cardiac hypertrophy. In addition, hearts were sectioned and H&E stained to evaluate myocyte size. Both TgGRK5 and WT mice exhibited a significant increase in myocyte size. Cardiac function was evaluated via echocardiography both prior to and after exercise training, and no changes were observed between TgGRK5 and WT mice after training. These data were re-affirmed in H9C2 cells and neonatal rat ventricular myocytes overexpressing either GFP or GRK5, which exhibited similar increases in cell size and AKT phosphorylation after IGF-1 treatment, a physiological hypertrophy stimulus. Taken together, these data suggest that physiological hypertrophy is similar in both control and TgGRK5 mice, confirming that GRK5 is solely a regulator of pathological cardiac hypertrophy.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01143.2007 ◽

2008 ◽

Vol 295 (3) ◽

pp. H1303-H1310 ◽

Cited By ~ 5

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.

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Effects of aging and subsequent exercise training on gene expression of endothelin-1 in rat heart

Clinical Science ◽

10.1042/cs103s152s ◽

2002 ◽

Vol 103 (s2002) ◽

pp. 152S-157S ◽

Cited By ~ 11

Author(s):

Motoyuki IEMITSU ◽

Takashi MIYAUCHI ◽

Seiji MAEDA ◽

Takumi TANABE ◽

Yoko IRUKAYAMA-TOMOBE ◽

...

Keyword(s):

Gene Expression ◽

Exercise Training ◽

Cardiac Hypertrophy ◽

Mrna Expression ◽

Natriuretic Peptide ◽

Young Group ◽

Aged Rats ◽

Aged Group ◽

Endothelin 1 ◽

Rat Hearts

Endothelin-1 (ET-1) is produced by endothelial cells and cardiac myocytes. ET-1 has potent positive inotropic and chronotropic effects on heart and induces myocardial cell hypertrophy. We investigated whether gene expression of ET-1 in rat hearts is altered by aging and subsequent exercise training. We also investigated whether gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which participate in some pathological cardiac conditions, in the rat hearts is altered by aging and subsequent exercise training. We studied mRNA expression of ET-1, ANP and BNP in hearts of sedentary young rats (Sedentary young; 4 months old), sedentary aged rats (Sedentary aged; 23 months old), and swim-trained aged rats (Trained aged; 23 months old, swimming training for 8 weeks). The left ventricle weight mass index for body weight and left ventricular end-diastolic dimension were significantly higher in the Trained aged group compared with the Sedentary aged group. These results showed that Trained aged rats developed cardiac hypertrophy with improvement of cardiac function. The mRNA expression of ET-1 in the heart was significantly higher in Sedentary aged group compared with Sedentary young group, and was significantly higher in the Trained aged group compared with the Sedentary aged group. The mRNA expression of ANP and BNP in the heart was significantly higher in Sedentary aged group compared with Sedentary young group, and was significantly higher in the Trained aged group compared with the Sedentary aged group. The present results show that mRNA expression of ET-1 in the heart is increased by aging, and that the mRNA expression is further increased by exercise-induced cardiac hypertrophy, suggesting that ET-1 in the heart may participate in these physiological cardiac adaptations.

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