Abstract 97: Histone Deacetylase Inhibition Prevents Cardiac Remodeling in Mice Carrying the Disruption of Guanylyl Cyclase/natriuretic Peptide Receptor-A Gene

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Umadevi Subramanian ◽  
Prerna Kumar ◽  
Kailash N Pandey
Keyword(s):  
Cardiac Hypertrophy ◽  
Histone Deacetylase ◽  
Sodium Butyrate ◽  
Cardiac Remodeling ◽  
Regulation Of Gene Expression ◽  
Heart Weight ◽  
Marker Genes ◽  
Dependent Manner ◽  
Histone Deacetylase Inhibition ◽  
Hdac Activity

Regulation of gene expression plays an obligatorily role in the modification of chromatin structure that dynamically attenuates cardiac hypertrophy. In order to culminate the role of epigenetic regulators in the heart tissue, the current study was undertaken to elucidate the effect of histone deacetylase (HDAC) inhibitor, sodium butyrate (SB) in cardiac remodeling process of Npr1 (coding for GC-A/NPRA) gene-targeted mice. Wild type ( Npr1 +/+ , 2-copy), gene-disrupted ( Npr1 +/- , 1-copy), and gene-duplicated ( Npr1 ++/+- , 3-copy) mice were administered intraperitoneally with SB (0.5 mg/kg/day) for 2 weeks (8 mice/group). Mice with gene-disruption ( Npr1 +/- , 1-copy) exhibited the increase in cardiac hypertrophy, heart weight/body weight (HW/BW) ratio (6.9 ± 0.2), and systolic blood pressure (SBP, 121.5 ± 4 mmHg) compared with 2-copy (HW/BW, 5.1 ± 0.2; SBP; 100.9 ± 6 mmHg) and 3-copy (HW/BW, 4.7 ± 0.1; SBP, 89.4 ± 2 mmHg) mice. In addition, an increased activity of HDAC (3-fold, p<0.01) and decreased activity of histone acetyltransferases (HAT) (2.5-fold, p<0.01) were found in untreated 1-copy mice hearts. Whereas, 1-copy mice treated with SB showed reduced HW/BW ratio (5.7 ± 0.3), SBP (SB, 101.2 ± 2), HDAC activity (p<0.01) and improved HAT activity (3-fold, p<0.001). Also, a stimulatory effect on HAT activity was observed in SB treated 2-copy (30%, p<0.01) and 3-copy (50%, p<0.01) mice. Furthermore, Npr1 +/- mice showed a significant increase in the expression of hypertrophic marker genes such as β-myosin heavy chain (β-MHC, 2-fold), α-skeletal actin (α-SK, 2-fold), c-fos (2.5-fold), and c-jun (3-fold) compared to untreated 2-copy and 3-copy mice. A substantial attenuation in the expression of hypertrophic markers (β-MHC, 2.5-fold; α-SK, 2.4-fold) and matrix genes (MMP-2, p<0.01; MMP-9, p<0.01) was found in SB-treated Npr1 +/- mice. The basal expression levels of matrix proteins were also significantly reduced in 2-copy and 3-copy mice hearts. The results show that sodium butyrate-dependent inhibition of HDAC activity attenuates cardiac hypertrophy and fibrosis by improving HAT activity suggesting that chromatin modification can prevent cardiac remodeling process in a Npr1 gene-dose-dependent manner.

Pygo1 regulates pathological cardiac hypertrophy via a β-catenin-dependent mechanism

2021 ◽  
Author(s):  
Li Lin ◽  
Wei Xu ◽  
Yongqing Li ◽  
Ping Zhu ◽  
Wuzhou Yuan ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Tissue ◽  
Heart Weight ◽  
Dependent Manner ◽  
Tissue Specific ◽  
Cardiac Tissues ◽  
Pathological Cardiac Hypertrophy ◽  
Interaction Factor ◽  
Myocardial Remodelling

Wnt/β-catenin signalling plays a key role in pathological cardiac remodelling in adults. The identification of a tissue-specific Wnt/β-catenin interaction factor may realise a tissue-specific clinical targeting strategy. Drosophila Pygo codes for the core interaction factor of Wnt/β-catenin. Two Pygo homologs, Pygo1 and Pygo2, have been identified in mammals. Different from the ubiquitous expression profile of Pygo2, Pygo1is enriched in cardiac tissue. However, the role of Pygo1 in mammalian cardiac disease remains unelucidated. Here, we found that Pygo1 was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios and increased cell size. The canonical β-catenin/T-cell transcription factor 4 complex was abundant in Pygo1-overexpressingtransgenic(Pygo1-TG) cardiac tissue,and the downstream genes of Wnt signaling, i.e., Axin2, Ephb3, and C-myc, were upregulated. A tail vein injection of β-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodelling in Pygo1-TG mice. Furthermore, in vivo downregulated pygo1 during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.

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).

scholarly journals Inhibition of Cardiac Hypertrophy Effects in D-Galactose-Induced Senescent Hearts byAlpinate Oxyphyllae FructusTreatment

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Yung-Ming Chang ◽  
Hen-Hong Chang ◽  
Hung-Jen Lin ◽  
Chin-Chuan Tsai ◽  
Chuan-Te Tsai ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Rat Model ◽  
Cerebrovascular Disorders ◽  
Treated Group ◽  
Left Ventricular ◽  
Heart Weight ◽  
Dependent Manner ◽  
Signaling Mechanism ◽  
Aging Rat ◽  
Whole Heart

Aging is a complex physiological phenomenon accelerated by ROS accumulation, with multisystem decline and increasing vulnerability to degenerative diseases and death. Cardiac hypertrophy is a key pathophysiological component that accompanies the aging process. Alpinate Oxyphyllae Fructus (Alpinia oxyphyllaMIQ, AOF) is a traditional Chinese medicine, which provides cardioprotective activity against aging, hypertension, and cerebrovascular disorders. In this study, we found the protective effect of AOF against cardiac hypertrophy in D-galactose-induced aging rat model. The results showed that treating rats with D-galactose resulted in pathological hypertrophy as evident from the morphology change, increased left ventricular weight/whole heart weight, and expression of hypertrophy-related markers (MYH7 and BNP). Both concentric and eccentric cardiac hypertrophy signaling proteins were upregulated in aging rat model. However, these pathological changes were significantly improved in AOF treated group (AM and AH) in a dose-dependent manner. AOF negatively modulated D-galactose-induced cardiac hypertrophy signaling mechanism to attenuate ventricular hypertrophy. These enhanced cardioprotective activities following oral administration of AOF reflect the potential use of AOF for antiaging treatments.

Abstract 265: CITED4 Induces Physiologic Hypertrophy and Improves Cardiac Remodeling After Ischemic Injury

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Vassilios J Bezzerides ◽  
Colin Platt ◽  
Kaavya Paruchuri ◽  
Loren Oh ◽  
Chunyang Xiao ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Gene Profiling ◽  
Neonatal Rat ◽  
Heart Weight ◽  
Autophagic Flux

Cardiac hypertrophy is an adaptive response to increased hemodynamic stresses, which can be either physiologic, as with exercise, or pathologic, as with valvular heart disease. Recent data suggest that physiologic hypertrophy secondary to exercise may be mediated by the transcription factor CEBPβ and the p300-interacting protein CITED4. We sought to investigate the cardiovascular effects of CITED4 expression in vivo. Using a cardiac-specific and inducible transgenic mouse (Tg) model, we determined the effects of CITED4 expression on cardiac parameters including heart weight, cell size, cardiac function and gene expression. Expression of CITED4 for 3 weeks induced increases in heart weight (22% in HW/TL, p < 0.01) and cardiomyocyte (CM) size (24.5% in cell area, p < 0.001) with normal systolic function and without evidence of fibrosis. Gene profiling demonstrated increased expression of cardiac troponin, a favorable αMHC/βMHC ratio and a reduction in BNP consistent with physiologic hypertrophy. Genome-wide expression profiling of neonatal rat ventricular myocytes (NRVMs) over-expressing CITED4 demonstrated the activation of a unique set of genes including BCL2, ATP12a, Efemp1, Ifi204 and Tcf19. To further examine the potential beneficial role of CITED4, we induced ischemia by transient occlusion of the left anterior descending (LAD) coronary (30 min) followed by reperfusion for 24 hours, 6 days or 4 weeks. At 24 hrs after ischemia-reperfusion injury (IRI), neither cardiac dysfunction on echo nor infarct sizes were different between CITED4 Tg and controls. However, CITED4 Tgs showed substantial recovery of cardiac function at 4 weeks (FS: CITED4 Tg 51%, Control 34%, p < 0.01) and a 3.4-fold reduction in fibrosis (p < 0.005). Analysis of possible cellular responses responsible for the functional recovery demonstrated enhanced autophagic flux with reduced accumulation of LC3II (down 71%, p<0.05) and p62 (down 54%, p<0.005). Further examination of the involved signaling pathway revealed direct activation of mTORC1 and its effectors consistent with a growth phenotype. We conclude that CITED4 expression is sufficient to induce physiologic cardiac hypertrophy and improves cardiac remodeling after ischemic injury likely through activation of mTORC1.

scholarly journals Polydatin prevents angiotensin II-induced cardiac hypertrophy and myocardial superoxide generation

2014 ◽  
Vol 240 (10) ◽  
pp. 1352-1361 ◽  
Author(s):  
Qi Zhang ◽  
Yingying Tan ◽  
Nan Zhang ◽  
Fanrong Yao
Keyword(s):  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Oxidase Activity ◽  
Weight Ratio ◽  
Heart Weight ◽  
Leucine Incorporation ◽  
Dependent Manner ◽  
Ang Ii ◽  
Nadph Oxidase Activity ◽  
Cultured Cardiomyocytes

Our studies and others recently demonstrate that polydatin, a resveratrol glucoside, has antioxidative and cardioprotective effects. This study aims to investigate the direct effects of polydatin on Ang II-induced cardiac hypertrophy to explore the potential role of polydatin in cardioprotection. Our results showed that in primary cultured cardiomyocytes, polydatin blocked Ang II-induced cardiac hypertrophy in a dose-dependent manner, which were associated with reduction in the cell surface area and [3H]leucine incorporation, as well as attenuation of the mRNA expressions of atrial natriuretic factor and β-myosin heavy chain. Furthermore, polydatin prevented rat cardiac hypertrophy induced by Ang II infusion, as assessed by heart weight-to-body weight ratio, cross-sectional area of cardiomyocyte, and gene expression of hypertrophic markers. Further investigation demonstrated that polydatin attenuated the Ang II-induced increase in the reactive oxygen species levels and NADPH oxidase activity in vivo and in vitro. Polydatin also blocked the Ang II-stimulated increases of Nox4 and Nox2 expression in cultured cardiomyocytes and the hearts of Ang II-infused rats. Our results indicate that polydatin has the potential to protect against Ang II-mediated cardiac hypertrophy through suppression of NADPH oxidase activity and superoxide production. These observations may shed new light on the understanding of the cardioprotective effect of polydatin.

Comparative cardioprotective effects of cromakalim and diltiazem in ischemic hypertrophied rat hearts

1996 ◽  
Vol 270 (1) ◽  
pp. H174-H182
Author(s):  
G. J. Grover ◽  
S. Dzwonczyk ◽  
T. M. Monticello
Keyword(s):  
Cardiac Hypertrophy ◽  
Contractile Function ◽  
Heart Weight ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Concentration Dependent Manner ◽  
Rat Hearts ◽  
Cardioprotective Effects ◽  
Ldh Release ◽  
Wistar Kyoto

Previous studies have indicated that alterations in cardiac ATP-sensitive potassium channels (KATP) can occur with cardiac hypertrophy. The goal of this study was to determine the effect of cardiac hypertrophy in spontaneously hypertensive rats (SHR) on the response to the cardioprotective agents diltiazem and cromakalim. Isolated rat hearts from 14-wk-old SHR, normotensive heterozygote Wistar-Kyoto (WKY), and Sprague-Dawley (SD) strains were subjected to 25 min of global ischemia and 30 min of reperfusion in the presence of vehicle (3-30 microM cromakalim or 0.1-1.0 microM diltiazem). SHR had heart weight-to-body weight ratios 40-50% greater than age-matched SD or WKY. Both diltiazem and cromakalim increased reperfusion contractile function in a concentration-dependent manner in SD rats as previously reported. Cromakalim and diltiazem caused similar improvements in reperfusion function in WKY rats and SHR. Cumulative lactate dehydrogenase (LDH) release during reperfusion was similar for vehicle-treated SD, WKY, or SHR hearts. LDH release was significantly attenuated by cromakalim and dilitiazem at all concentrations tested in SD and WKY hearts, whereas LDH release was not attenuated in SHR hearts by any concentration of cromakalim or diltiazem tested. Morphological assessment of hearts by light microscopy indicated that the severity and distribution of myocardial lesions were not affected by cromakalim in SHR hearts, compared with vehicle-treated SHR, supporting the LDH data. These results suggest that in SHR hearts, cromakalim and dilitiazan may exert much of their cardioprotective effects on the population of myocytes that are not irreversibly damaged.

scholarly journals Casein Kinase-2 Interacting Protein-1 Regulates Physiological Cardiac Hypertrophy via Inhibition of Histone Deacetylase 4 Phosphorylation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yinlong Zhao ◽  
Shukuan Ling ◽  
Guohui Zhong ◽  
Yuheng Li ◽  
Jianwei Li ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Histone Deacetylase ◽  
Cardiac Remodeling ◽  
Physiological Stress ◽  
Exercise Program ◽  
Casein Kinase ◽  
Swimming Exercise ◽  
Interacting Protein ◽  
Physiological Cardiac Hypertrophy ◽  
Histone Deacetylase 4

Different kinds of mechanical stimuli acting on the heart lead to different myocardial phenotypes. Physiological stress, such as exercise, leads to adaptive cardiac hypertrophy, which is characterized by a normal cardiac structure and improved cardiac function. Pathological stress, such as sustained cardiac pressure overload, causes maladaptive cardiac remodeling and, eventually, heart failure. Casein kinase-2 interacting protein-1 (CKIP-1) is an important regulator of pathological cardiac remodeling. However, the role of CKIP-1 in physiological cardiac hypertrophy is unknown. We subjected wild-type (WT) mice to a swimming exercise program for 21 days, which caused an increase in myocardial CKIP-1 protein and mRNA expression. We then subjected CKIP-1 knockout (KO) mice and myocardial-specific CKIP-1-overexpressing mice to the 21-day swimming exercise program. Histological and echocardiography analyses revealed that CKIP-1 KO mice underwent pathological cardiac remodeling after swimming, whereas the CKIP-1-overexpressing mice had a similar cardiac phenotype to the WT controls. Histone deacetylase 4 (HDAC4) is a key molecule in the signaling cascade associated with pathological hypertrophy; the phosphorylation levels of HDAC4 were markedly higher in CKIP-1 KO mouse hearts after the swimming exercise program. The phosphorylation levels of HDAC4 did not change after swimming in the hearts of CKIP-1-overexpressing or WT mice. Our results indicate that swimming, a mechanical stress that leads to physiological hypertrophy, triggers pathological cardiac remodeling in CKIP-1 KO mice. CKIP-1 is necessary for physiological cardiac hypertrophy in vivo, and for modulating the phosphorylation level of HDAC4 after physiological stress. Genetically engineering CKIP-1 expression affected heart health in response to exercise.

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