Abstract 65: Regulation of Cardiac Hypertrophy and Dilated Cardiomyopathy by CIP

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Zhan-Peng Huang ◽  
Masaharu Kataoka ◽  
Jinghai Chen ◽  
Da-Zhi Wang
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Premature Death ◽  
Marker Genes ◽  
Ontology Term ◽  
Hypertrophic Growth

Cardiac hypertrophy is one of the primary responses of the heart to pathophysiological stress. However, the mechanism of the transition from compensative hypertrophic growth to cardiac dilation is poor understood. Recently, we identified a cardiac-specific expressed gene CIP. The expression of CIP is unchanged in hypertrophic heart but significantly down-regulated in dilated hearts, suggesting CIP may play an important role in the transition from cardiac hypertrophy to dilated cardiomyopathy. We generated CIP knockout mice and found that CIP is dispensable for cardiac development. Interestingly, CIP-null mutant mice developed severe cardiac dilation 4 weeks after TAC (transverse aortic constriction) surgery, while control mice were still at the stage of compensative hypertrophic growth. Echocardiography and histological examinations showed that mutant hearts had enlarged chamber with thinner ventricle wall and decreased cardiac performance compared to controls. The expression of marker genes of cardiac disease, BNP and Myh7, was elevated. Consistently, deletion of CIP in Myh6-CnA transgenic mice result in premature death, displaying severe left ventricle dilation. Conversely, cardiac-specific CIP overexpression inhibited pressure overload-induced cardiac hypertrophy. CIP transgenic mice exhibit decreased ventricle weight/body weight ratio, decreased cardiomyocyte cross-section area and repressed expression of hypertrophic related marker genes. CIP overexpression also protected the heart from developing cardiac dilation and preserved the cardiac function after prolonged pressure overload. We performed unbiased microarray assay to document the transcriptome in CIP knockout and control mice which were subjected to pressure overload (TAC). The analysis of Gene Ontology term indicated the Negative Regulation of Apoptosis was down-regulated while the Collagen/Extracellular Structure Organization was up-regulated in CIP-null hearts under TAC condition. In summary, our studies established CIP as a key regulator of the transition from cardiac hypertrophy to dilated cardiomyopathy. The protective effect of CIP in cardiac remodeling indicates that CIP could become a therapeutic target for cardiac diseases.

Abstract 241: Cardiac-Specific Overexpression of Runx2 Mediates Cardiac Hypertrophy and Dysfunction in Mice

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Hiroyuki Nakayama ◽  
Tatsuto Hamatani ◽  
Shohei Kumagai ◽  
Kota Tonegawa ◽  
Tomomi Yamashita ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Premature Death ◽  
Heart Weight ◽  
Pcr Analysis ◽  
Marker Genes ◽  
Hypertrophic Response ◽  
Neonatal Cardiomyocytes

Backgrounds: Recent studies demonstrated that the osteopontin (OPN), an acid phosphoprotein plays pivotal roles in cardiac hypertrophy and failure. An osteogenic transcription factor Runx2 regulates the expression of OPN in osteoblasts. In the present study, we examined the pathological role of Runx2 in cardiac hypertrophy and failure. Methods and Results: Runx2 expression was detected in neonatal cardiomyocytes and upregulated in heart 14 days after myocardial infarction (MI) as well as 7days after transverse aortic constriction (TAC) procedures. To determine the functional role of Runx2 in heart, we generated transgenic mice (TG) with inducible cardiac-specific overexpression of Runx2. Two TG lines (low and high) were obtained and high-expressing TG (HE-TG) showed premature death within 8 weeks of age specifically in male mice. At two months of age, the survived male and female HE-TG displayed significant increases in heart weight/body weight ratio (mg/g) compared to controls (control; 4.95±0.26, n=6 vs HE-TG; 6.63±0.12, n=5, p<.05). Consistent with those results, the expression of hypertrophic marker genes such as atrial natriuretic factor (ANF) and αskeletal actin significantly increased in HE-TG heart assessed by real-time RT-PCR analysis. In addition, HE-TG mice demonstrated decreased fractional shortening assessed by echocardiography (control; 44.1±1.89%, n=9 vs HE-TG; 23.9±3.48%, n=7, p<.05). HE-TG mice demonstrated significantly lower heart rate (control; 630±18 bpm, vs HE-TG; 350±74 bpm, n=3 each, p<.05) and complete atrioventricular block by telemetry analysis. In response to pressure overload, low expressing TG (LE-TG) demonstrated higher mortality and enhanced cardiac hypertrophic response after TAC (control; 6.20±0.23, n=6 vs LE-TG; 6.90±0.26, n=4, p<.05). Conclusions: Targeted expression of Runx2 in heart mediates cardiac dysfunction and hypertrophy in mice. Thus, Runx2 could be a novel therapeutic target for heart failure.

scholarly journals Cooperative Binding of ETS2 and NFAT Link Erk1/2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy

Circulation ◽  
2021 ◽  
Author(s):  
Yuxuan Luo ◽  
Nan Jiang ◽  
Herman I. May ◽  
Xiang Luo ◽  
Anwarul Ferdous ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Target Genes ◽  
Critical Role ◽  
Pressure Overload ◽  
Marker Genes ◽  
Activated T Cells ◽  
Hypertrophic Growth ◽  
Conditional Deletion ◽  
Extracellular Signal

Background: Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an inter-dependent network of signaling cascades. However, how these pathways interact remains unclear, and specifically few direct targets responsible for the pro-hypertrophic role of NFAT have been described. Methods: By engineering a cardiomyocyte-specific ETS2 (a member of E26 transformationspecific sequence (ETS)-domain family) knockout mice, we investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were also used to evaluate ETS2 function in cell growth. Results: ETS2 is phosphorylated and activated by Erk1/2 upon hypertrophic stimulation in both mouse (n = 3) and human heart samples (n = 8-19). Conditional deletion of ETS2 in mouse cardiomyocytes protects against pressure overload-induced cardiac hypertrophy (n = 6-11). Furthermore, silencing of ETS2 in the hearts of calcineurin transgenic mice significantly attenuates hypertrophic growth and contractile dysfunction (n = 8). As a transcription factor, ETS2 is capable of binding to the promoters of hypertrophic marker genes, such as ANP, BNP and Rcan1.4 (n = 4). Additionally, we report that ETS2 forms a complex with NFAT to stimulate transcriptional activity through increased NFAT binding to the promoters of at least two hypertrophy-stimulated genes, Rcan1.4 and miR-223 (n = 4-6). Suppression of miR-223 in cardiomyocytes inhibits calcineurin-mediated cardiac hypertrophy (n = 6), revealing miR-223 as a novel pro-hypertrophic target of the calcineurin-NFAT and Erk1/2-ETS2 pathways. Conclusions: In aggregate, our findings point to a critical role for ETS2 in calcineurin-NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.

scholarly journals The c-myc proto-oncogene regulates cardiac development in transgenic mice.

1990 ◽  
Vol 10 (7) ◽  
pp. 3709-3716 ◽  
Author(s):  
T Jackson ◽  
M F Allard ◽  
C M Sreenan ◽  
L K Doss ◽  
S P Bishop ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Mrna Expression ◽  
Cardiac Myocyte ◽  
Cellular Proliferation ◽  
Cardiac Development ◽  
Constitutive Expression ◽  
Transgenic Animals ◽  
Hypertrophic Growth ◽  
Myocyte Proliferation

During the maturation of the cardiac myocyte, a transition occurs from hyperplastic to hypertrophic growth. The factors that control this transition in the developing heart are unknown. Proto-oncogenes such as c-myc have been implicated in the regulation of cellular proliferation and differentiation, and in the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc can influence myocyte proliferation or differentiation, we examined the in vivo effect of increasing c-myc expression during embryogenesis and of preventing the decrease in c-myc mRNA expression that normally occurs during cardiac development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. In these transgenic mice, increased c-myc mRNA expression was found to be associated with both atrial and ventricular enlargement. This increase in cardiac mass was secondary to myocyte hyperplasia, with the transgenic hearts containing more than twice as many myocytes as did nontransgenic hearts. The results suggest that in the transgenic animals there is additional hyperplastic growth during fetal development. However, this additional proliferative growth is not reflected in abnormal myocyte maturation, as assessed by the expression of the cardiac and skeletal isoforms of alpha-actin. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth and suggest a regulatory role for this proto-oncogene in cardiac myogenesis.

Abstract 1372: Characterization Of The Rejuvenation Of Cardiac Sympathetic Nerves In Cardiac Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Kensuke Kimura ◽  
Masaki Ieda ◽  
Hideaki Kanazawa ◽  
Takahide Arai ◽  
Takashi Kawakami ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Fluorescent Protein ◽  
Sympathetic Neurons ◽  
Weight Ratio ◽  
Sympathetic Nerves ◽  
Marker Genes ◽  
List Type ◽  
Stellate Ganglia ◽  
Immature Neuron

Background : Cardiac hypertrophy induces the fetal isoform of genes (rejuvenation), including contractile proteins, ion channels, and natriuretic peptides. Cardiac sympathetic nerve function is known to be altered in cardiac hypertrophy and congestive heart failure. We recently reported that alteration of cardiac sympathetic nerves (CSN) was caused by their rejuvenation (Circ Res, 2007). The present study was designed to examine the precise characterization of the rejuvenation of CSN in cardiac hypertrophy. Methods and Results : RV hypertrophy was produced by consistent hypoxia (10% O 2 ) in C57/BL6 mice. RV pressure increased to 47 mmHg, and RV/(body weight) ratio increased by 1.6 fold. Nerve growth factor protein was augmented in hypertrophic RV, but was unchanged in LV. Double-transgenic mice, which specifically express eGFP (enhanced green fluorescent protein) in the sympathetic neurons, was generated by crossing dopamine β-hydroxylase (DBH)-Cre mice with Floxed-eGFP mice. The eGFP-positive CSN were markedly increased in hypertrophic RV, but not in LV. Nerve density, quantitated by immunostained area with eGFP and GAP43 (growth-associated corn marker), increased by 8.1 and 9.3 fold, respectively, in RV, but not in LV. (4) Catecholamine content was attenuated in RV. (5) Western blot revealed that tyrosine hydroxylase was markedly down-regulated in RV. (6) Immunostaining clearly demonstrated that the immature neuron markers, PSA-NCAM (highly polysialylated neural cell adhesion molecule) and Ulip-1 (Unc-33-like phosphoprotein 1), were expressed in CSN in hypertrophic RV and stellate ganglia. Basic helix-loop-helix transcription factor, Mash-1 (mammalian achaete-scute complex homolog 1) was strongly expressed in the stellate ganglia. (7) Immature neuron marker-immunopositive cells in stellate ganglia had a markedly decreased TH expression. Conclusion : The rejuvenated CSN showed various immature and fetal neuron marker genes at not only the peripheral axons but also the cellular bodies at the stellate ganglia. Rejuvenation of CSN might be critically involved in the alteration of sympathetic neuronal function in cardiac hypertrophy, including depressed norepinephrine synthesis and hyperinnervation.

Abstract 3773: Myotrophin and the p53 Signaling Cascade in Cardiac Hypertrophy/Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Biswajit Das ◽  
David Young ◽  
Amit Vasanji ◽  
Sudhiranjan Gupta ◽  
Zoran Popovic ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Expression Profiles ◽  
Gene Array ◽  
Weight Ratio ◽  
Signaling Cascade ◽  
Mobility Shift ◽  
Transgenic Mouse Line ◽  
P53 Signaling

Myotrophin (Myo), a 12-kDa protein, stimulates myocyte growth and is a factor in initiating cardiac hypertrophy (CH). Cardiospecific overexpression of Myo in transgenic mice (Myo-Tg) induces hypertrophy that progresses to heart failure (HF). Oligonucleotide gene array revealed upregulation of a p53 homologue gene (EST- AI843106 ) in Myo-Tg mice during HF, indicating that p53 plays an important role during the transition of hypertrophy to HF. To dissect out the mechanisms of p53-mediated Myo-induced CH/HF, we developed a double-transgenic mouse line (p53 −/− /myo +/+ ) by crossing Myo-Tg mice with p53-null mice. The double transgenic mice showed a significant attenuation of cardiac mass compared to Myo-Tg mice (heart weight:body weight ratio; 5.2 ± 0.21 vs. 7.9 ± 0.58, p < 0.001) associated with improved cardiac function and downregulation of ANF expression, suggesting that hypertrophy induced by Myo overexpression is indeed mediated through p53. To elucidate the relationship between p53 and Myo-induced hypertrophy, we performed a Reverse-Transcription Real-Time PCR pathway array on heart tissues from p53 −/− /myo +/+ vs. Myo-Tg mice. A bioinformatic approach, Ingenuity Pathway Analysis TM (IPA), was used to analyze the selected up-/downregulated genes. The IPA network showed that among the up-/downregulated genes, Bcl2, Brca1, Cdkn1a and Myc occupy the nodal position, whereas E2f1 , Pmaip1 , Gadd45a and Pttg1 function as peripheral candidates. The expression profiles of some genes of the p53 pathway were validated by immunoblot analysis. Functional assignment of these selected candidate genes showed that Bcl2, E2f1 and FasL are related to CH/HF, but the function of Gadd45a, Pmaip1, and Vcan is still unknown. Apart from these p53 cascade members, we also found that other molecules (e.g., Jnk, Ras, NF-kB, Cyclin L, and Mek) may be involved in an intricate interplay to stimulate p53-mediated Myo-induced CH. Suppression of NF-kB activity (by electrophoresis mobility shift assay) in p53 −/− /myo +/+ mice compared to Myo-Tg mice indicated involvement of NF-kB, as predicted by IPA, in Myo/p53 cross-talk. Our data suggest that the p53 signaling cascade actively participates in progression of hypertrophy to HF, triggered by overexpression of myotrophin.

scholarly journals Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling

Hypertension ◽  
2021 ◽  
Author(s):  
Yuhao Zhang ◽  
Sheng-an Su ◽  
Wudi Li ◽  
Yuankun Ma ◽  
Jian Shen ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Ion Channel ◽  
Calcium Homeostasis ◽  
Pressure Overload ◽  
Cell Physiology ◽  
Hypertrophic Growth ◽  
Molecular Features ◽  
Mechanosensitive Ion Channel

Hemodynamic overload induces pathological cardiac hypertrophy, which is an independent risk factor for intractable heart failure in long run. Beyond neurohumoral regulation, mechanotransduction has been recently recognized as a major regulator of cardiac hypertrophy under a myriad of conditions. However, the identification and molecular features of mechanotransducer on cardiomyocytes are largely sparse. For the first time, we identified Piezo1 (Piezo type mechanosensitive ion channel component 1), a novel mechanosensitive ion channel with preference to Ca 2+ was remarkably upregulated under pressure overload and enriched near T-tubule and intercalated disc of cardiomyocyte. By applying cardiac conditional Piezo1 knockout mice (Piezo1 fl/fl Myh6Cre+, Piezo1 Cko ) undergoing transverse aortic constriction, we demonstrated that Piezo1 was required for the development of cardiac hypertrophy and subsequent adverse remodeling. Activation of Piezo1 by external mechanical stretch or agonist Yoda1 lead to the enlargement of cardiomyocytes in vitro, which was blocked by Piezo1 silencing or Yoda1 analog Dooku1 or Piezo1 inhibitor GsMTx4. Mechanistically, Piezo1 perturbed calcium homeostasis, mediating extracellular Ca 2+ influx and intracellular Ca 2+ overload, thereby increased the activation of Ca 2+ -dependent signaling, calcineurin, and calpain. Inhibition of calcineurin or calpain could abolished Yoda1 induced upregulation of hypertrophy markers and the hypertrophic growth of cardiomyocytes in vitro. From a comprehensive view of the cardiac transcriptome, most of Piezo1 affected genes were highly enriched in muscle cell physiology, tight junction, and corresponding signaling. This study characterizes an undefined role of Piezo1 in pressure overload induced cardiac hypertrophy. It may partially decipher the differential role of calcium under pathophysiological condition, implying a promising therapeutic target for cardiac dysfunction.

The c-myc proto-oncogene regulates cardiac development in transgenic mice

1990 ◽  
Vol 10 (7) ◽  
pp. 3709-3716
Author(s):  
T Jackson ◽  
M F Allard ◽  
C M Sreenan ◽  
L K Doss ◽  
S P Bishop ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Mrna Expression ◽  
Cardiac Myocyte ◽  
Cellular Proliferation ◽  
Cardiac Development ◽  
Constitutive Expression ◽  
Transgenic Animals ◽  
Hypertrophic Growth ◽  
Myocyte Proliferation

During the maturation of the cardiac myocyte, a transition occurs from hyperplastic to hypertrophic growth. The factors that control this transition in the developing heart are unknown. Proto-oncogenes such as c-myc have been implicated in the regulation of cellular proliferation and differentiation, and in the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc can influence myocyte proliferation or differentiation, we examined the in vivo effect of increasing c-myc expression during embryogenesis and of preventing the decrease in c-myc mRNA expression that normally occurs during cardiac development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. In these transgenic mice, increased c-myc mRNA expression was found to be associated with both atrial and ventricular enlargement. This increase in cardiac mass was secondary to myocyte hyperplasia, with the transgenic hearts containing more than twice as many myocytes as did nontransgenic hearts. The results suggest that in the transgenic animals there is additional hyperplastic growth during fetal development. However, this additional proliferative growth is not reflected in abnormal myocyte maturation, as assessed by the expression of the cardiac and skeletal isoforms of alpha-actin. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth and suggest a regulatory role for this proto-oncogene in cardiac myogenesis.

Abstract 080: Eya4 Induces Hypertrophy Via Regulation Of p27kip1

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Tatjana Williams ◽  
Moritz Hundertmark ◽  
Peter Nordbeck ◽  
Sabine Voll ◽  
Melanie Muehlfelder ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Pressure Overload ◽  
Dominant Negative ◽  
Heart Weight ◽  
Dominant Negative Effect ◽  
Mutant Form ◽  
Cardiac Phenotype ◽  
Truncating Mutation

Introduction: E193, a truncating mutation in the transcription cofactor Eyes absent 4 (Eya4) causes hearing impairment followed by heart failure. Here we identified the Eya4 dependent molecular mechanisms leading to the cardiac phenotype in the E193 mutation. Methods and Results: First we showed in vitro that the cyclin-dependent kinase inhibitor protein p27kip1 is a direct target of Eya4/Six1 and is suppressed upon Eya4 overexpression, whereas E193 has a dominant negative effect, releasing Eya4 mediated suppression of p27. We next generated transgenic mice with cardiac specific constitutive overexpression of full-length Eya4 or the mutant form E193. While E193 transgenic mice developed age-dependent DCM, Eya4 mice displayed cardiac hypertrophy already under basal conditions as judged by increases in heart weight and cardiomyocyte cross-sectional areas along with increases in myocardial dimension and mass. These two distinct cardiac phenotypes were even more aggravated upon pressure overload suggesting Eya4 is a regulator of cardiac hypertrophy. We also observed that the activity of Casein Kinase 2-α and the phosphorylation status of HDAC2 were significantly upregulated in the Eya4 transgenic mice, while they were significantly reduced in E193 mice, under baseline conditions and pressure overload. We were also able to identify a new human mutation (E215) with a phenotype comparable to the one seen in E193 patients. Conclusion: Our results implicate that Eya4/Six1 regulates cardiac hypertrophic reactions via p27/CK2-α/HDAC2 and indicate that truncating mutations in Eya4 interfere with this newly established signalling pathway.

scholarly journals Transcription factor CHF1/Hey2 suppresses cardiac hypertrophy through an inhibitory interaction with GATA4

2006 ◽  
Vol 290 (5) ◽  
pp. H1997-H2006 ◽  
Author(s):  
Fan Xiang ◽  
Yasuhiko Sakata ◽  
Lei Cui ◽  
Joey M. Youngblood ◽  
Hironori Nakagami ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transgenic Mice ◽  
Cardiac Hypertrophy ◽  
Marker Genes ◽  
Recognition Sequence ◽  
Inhibitory Interaction ◽  
Hypertrophic Response ◽  
Neonatal Cardiomyocytes

Pathological cardiac hypertrophy is considered a precursor to clinical heart failure. Understanding the transcriptional regulators that suppress the hypertrophic response may have profound implications for the treatment of heart disease. We report the generation of transgenic mice that overexpress the transcription factor CHF1/Hey2 in the myocardium. In response to the α-adrenergic agonist phenylephrine, they show marked attenuation in the hypertrophic response compared with wild-type controls, even though blood pressure is similar in both groups. Isolated myocytes from transgenic mice demonstrate a similar resistance to phenylephrine-induced hypertrophy in vitro, providing further evidence that the protective effect of CHF1/Hey2 is mediated at the myocyte level. Induction of the hypertrophy marker genes ANF, BNP, and β- MHC in the transgenic cells is concurrently suppressed in vivo and in vitro, demonstrating that the induction of hypertrophy-associated genes is repressed by CHF1/Hey2. Transfection of CHF1/Hey2 into neonatal cardiomyocytes suppresses activation of an ANF reporter plasmid by the transcription factor GATA4, which has previously been shown to activate a hypertrophic transcriptional program. Furthermore, CHF1/Hey2 binds GATA4 directly in coimmunoprecipitation assays and inhibits the binding of GATA4 to its recognition sequence within the ANF promoter. Our findings demonstrate that CHF1/Hey2 functions as an antihypertrophic gene, possibly through inhibition of a GATA4-dependent hypertrophic program.

scholarly journals The bHLH transcription factor CHF1/Hey2 regulates susceptibility to apoptosis and heart failure after pressure overload

2010 ◽  
Vol 298 (6) ◽  
pp. H2082-H2092 ◽  
Author(s):  
Yonggang Liu ◽  
Man Yu ◽  
Ling Wu ◽  
Michael T. Chin
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Heart Tissue ◽  
Tunel Staining ◽  
Bhlh Transcription Factor ◽  
Gravimetric Analysis ◽  
Aortic Banding

Cardiac hypertrophy is a common response to hemodynamic stress in the heart and can progress to heart failure. To investigate whether the transcription factor cardiovascular basic helix-loop-helix factor 1/hairy/enhancer of split related with YRPW motif 2 (CHF1/Hey2) influences the development of cardiac hypertrophy and progression to heart failure under conditions of pressure overload, we performed aortic constriction on 12-wk-old male wild-type (WT) and heterozygous (HET) mice globally underexpressing CHF1/Hey2. After aortic banding, WT and HET mice showed increased cardiac hypertrophy as measured by gravimetric analysis, as expected. CHF1/Hey2 HET mice, however, demonstrated a greater increase in the ventricular weight-to-body weight ratio compared with WT mice ( P < 0.05). Echocardiographic measurements showed a significantly decreased ejection fraction compared with WT mice ( P < 0.05). Histological examination of Masson trichrome-stained heart tissue demonstrated extensive fibrosis in HET mice compared with WT mice. TUNEL staining demonstrated increased apoptosis in HET hearts ( P < 0.05). Exposure of cultured neonatal myocytes from WT and HET mice to H2O2 and tunicamycin, known inducers of apoptosis that work through different mechanisms, demonstrated significantly increased apoptosis in HET cells compared with WT cells ( P < 0.05). Expression of Bid, a downstream activator of the mitochondrial death pathway, was expressed in HET hearts at increased levels after aortic banding. Expression of GATA4, a transcriptional activator of cardiac hypertrophy, was also increased in HET hearts, as was phosphorylation of GATA4 at Ser105. Our findings demonstrate that CHF1/Hey2 expression levels influence hypertrophy and the progression to heart failure in response to pressure overload through modulation of apoptosis and GATA4 activity.

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