P4999Cardiomyocyte ErbB4 receptors are essential for developmental cardiac hypertrophy and cardiac function in adult hearts

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Reichelt ◽  
Z Wang ◽  
C Thorn ◽  
T Paravicini ◽  
W G Thomas
Keyword(s):  
Cardiac Hypertrophy ◽  
Dilated Cardiomyopathy ◽  
Heart Development ◽  
Contractile Function ◽  
Critical Role ◽  
Tamoxifen Treatment ◽  
Cardiomyocyte Hypertrophy ◽  
Adult Heart ◽  
Neonatal Mice

Abstract Background/Introduction Activation of ErbB4 by neuregulin 1 (NRG1) promotes cardiomyocyte hypertrophy and proliferation in both adult and neonatal mice, while treatment of patients with NRG1 following myocardial infarction reduces scar size and improves function. In mice, deletion of ErbB4 from cardiomyocytes mid-gestation results in development of dilated cardiomyopathy and reduced survival, pointing to a critical role for ErbB4 in the heart. Purpose We sought to evaluate the role of ErbB4 in the adult heart. Methods and results We deleted ErbB4 in αMHC-MerCreMer (cCre Tg+/)/ErbB4 homozygote floxed (ErbB4 fl/fl) mice at ∼2 months of age with 10 injections of Tamoxifen (20 mg/kg/day). Contractile function was reduced in vivo (echocardiography, 16%) and ex vivo (isolated-perfused, 33%) 3 months after gene deletion, while survival in mice up to 8 months after tamoxifen treatment was mot modified by cardiomyocyte ErbB4 deletion. We next evaluated the role of ErbB4 in response to physiological and pathological hypertrophic stressors. ErbB4 deletion did not modify cardiac enlargement in response to Angiotensin II (1000ng/kg/min, 14 days) or exercise (twice daily swimming, 20 min/session increasing 10 min/day to 90 min followed by 7 days at 90 min/session). Taken together, this indicated that ErbB4 is not essential for survival and adaptation in the adult heart, pointing instead towards a critical window for ErbB4 in neonatal heart development. To test this hypothesis, ErbB4ff and ErbB4ww neonates were injected at P1 with AAV9-cTNT-eGFP-iCre (2.16x1011viral particles, temporal vein) and culled at P6. We confirmed the presence of iCre mRNA, and suppression of ErbB4 in ErbB4 ff/ff mice, coincident with increased NRG1a, and reduced body and ventricular weights. By day 28, a number of hearts showed evidence of dilated cardiomyopathy. Conclusion Thus, ErbB4 is critical to cardiac hypertrophy and growth in neonatal mice, and maintains adult heart function. Acknowledgement/Funding National Health and Medical Research Council

Abstract 309: Small Heterodimer Partner Blocks Cardiac Hypertrophy By Interfering With GATA6 Signaling

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Yoon Seok Nam ◽  
Duk-Hwa Kwon ◽  
Gwang Hyeon Eom ◽  
Hyun Kook
Keyword(s):  
Cardiac Hypertrophy ◽  
Heart Diseases ◽  
Cardiomyocyte Hypertrophy ◽  
Physical Interaction ◽  
Orphan Nuclear Receptor ◽  
Promoter Regions ◽  
Adult Heart ◽  
Hypertrophic Response ◽  
Small Heterodimer Partner

Rationale: Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA binding domain. By interacting with other transcription factors, SHP regulates diverse biological events including glucose metabolism in liver. The role of SHP in adult heart diseases has not yet been demonstrated. Objective: We aimed to investigate the role of SHP in adult heart in association with cardiac hypertrophy. Methods and Results: The roles of SHP in cardiac hypertrophy were tested in primary cultured cardiomyocytes and in animal models. SHP null mice showed a hypertrophic phenotype. Hypertrophic stresses repressed the expression of SHP, whereas forced expression of SHP blocked the development of cardiomyocyte hypertrophy. SHP reduced the protein amount of Gata6. By direct physical interaction with Gata6, SHP interfered with the binding of Gata6 to GATA binding elements in the promoter regions of natriuretic peptide precursor type A. Metformin, an anti-diabetic agent, induced SHP and suppressed cardiac hypertrophy. The metformin-induced anti-hypertrophic effect was attenuated either by SHP siRNA in cardiomyocytes or in SHP null mice. Conclusions: These results establish SHP as a novel anti-hypertrophic regulator that acts by interfering with GATA6 signaling. SHP may participate in the metformin-induced anti-hypertrophic response.

Abstract 69: Cardiomyocyte GSK-3α Signaling Exacerbate Pressure Overload-induced Dilated Cardiomyopathy and Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Firdos Ahmad ◽  
Hind Lal ◽  
Vipin K Verma ◽  
Qinkun Zhang ◽  
James R Woodgett ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Glycogen Synthase ◽  
Contractile Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Tamoxifen Treatment ◽  
Control Group ◽  
Lv Remodeling

Chronic pressure-overload (PO) induced-dilated cardiomyopathy (DCM) is one of the leading causes of left ventricular (LV) remodeling and heart failure. The role of glycogen synthase kinase-3α (GSK-3α) in PO-induced remodeling is not clear and existing dataset with global transgenic and knockout (KO) models show opposing roles. We sought to identify the specific role of GSK-3α in PO-induced dilatative cardiac remodeling. To better understand the role of GSK-3α, we employed cardiomyocyte-specific GSK3A ( GSK3A fl/fl MerCreMer ) KO mice. Post-tamoxifen treatment, the GSK-3α KO and littermate control mice underwent sham or trans-aortic constriction (TAC) surgery. Heart function was assessed at 0, 2, 4 and 6 week post-TAC using serial M-mode echocardiography. Cardiac function in the KOs and littermate controls declines equally up to 2 weeks of TAC. At 4 week, KO hearts underwent further hypertrophy, retaining concentric LV remodeling and preserved contractile function both at systole and diastole. In contrast, wild-type LV showed significant chamber dilatation with an impaired contractility. Significantly reduced LV chamber dilatation [LVIDd(mm); 5.4±0.4 vs. 4.9±0.4, P =0.01] and preserved contractile function [LVEF(%); 22.2±12.6 vs. 40.0±18.7, P =0.02] remains same in the KO mice until the end of the study (6 wk). Furthermore, LV posterior wall thickness in the KO hearts, both at systole and diastole, were significantly greater in comparison to the controls. Consistent with preserved LV dimension, significantly less mortality was observed in the KO vs. control group during the remodeling phase. Histological analysis of heart sections further revealed better preserved LV chamber and protection against TAC-induced cellular hypertrophy in the GSK-3α KOs. Moreover, KO hearts showed significantly less fibrosis accompanied with low level of cardiomyocyte apoptosis post-6 wk of TAC. Taken together, these observations show that cardiomyocyte-specific deletion of GSK-3α protects against chronic PO-induced adverse LV remodeling and preserves contractile function. Inhibiting specifically GSK-3α using isoform-specific inhibitor could be a viable therapeutic strategy to limit the PO-induced DCM, adverse remodeling and heart failure.

scholarly journals Deubiquitinase Ubiquitin‐Specific Protease 10 Deficiency Regulates Sirt6 signaling and Exacerbates Cardiac Hypertrophy

2020 ◽  
Vol 9 (22) ◽  
Author(s):  
Dian‐Hong Zhang ◽  
Jie‐Lei Zhang ◽  
Zhen Huang ◽  
Lei‐Ming Wu ◽  
Zhong‐Min Wang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Contractile Function ◽  
Pressure Overload ◽  
Cysteine Proteases ◽  
Cardiomyocyte Hypertrophy ◽  
Aortic Banding ◽  
Isolated Cardiomyocytes ◽  
Specific Protease ◽  
Ubiquitin Specific Protease

Background Cardiac hypertrophy (CH) is a physiological response that compensates for blood pressure overload. Under pathological conditions, hypertrophy can progress to heart failure as a consequence of the disorganized growth of cardiomyocytes and cardiac tissue. USP10 (ubiquitin‐specific protease 10) is a member of the ubiquitin‐specific protease family of cysteine proteases, which are involved in viral infection, oxidative stress, lipid drop formation, and heat shock. However, the role of USP10 in CH remains largely unclear. Here, we investigated the roles of USP10 in CH. Methods and Results Cardiac‐specific USP10 knockout (USP10‐CKO) mice and USP10‐transgenic (USP10‐TG) mice were used to examined the role of USP10 in CH following aortic banding. The specific functions of USP10 were further examined in isolated cardiomyocytes. USP10 expression was increased in murine hypertrophic hearts following aortic banding and in isolated cardiomyocytes in response to hypertrophic agonist. Mice deficient in USP10 in the heart exhibited exaggerated cardiac hypertrophy and fibrosis following pressure overload stress, which resulted in worsening of cardiac contractile function. In contrast, cardiac overexpression of USP10 protected against pressure overload‐induced maladaptive CH. Mechanistically, we demonstrated that USP10 activation and interaction with Sirt6 in response to angiotensin II led to a marked increase in the ubiquitination of Sirt6 and resulted in Akt signaling downregulation and attenuation of cardiomyocyte hypertrophy. Accordingly, inactivation of USP10 reduced Sirt6 abundance and stability and diminished Sirt6‐induced downstream signaling in cardiomyocytes. Conclusions USP10 functions as a Sirt6 deubiquitinase that induces cardiac myocyte hypertrophy and triggers maladaptive CH.

scholarly journals A CRITICAL ROLE OF TRPC1-ORAI1-STIM1 MEDIATED STORE OPERATED CALCIUM ENTRY IN CARDIAC HYPERTROPHY

2015 ◽  
Vol 65 (10) ◽  
pp. A902
Author(s):  
Senthil Selvaraj ◽  
Brij Singh ◽  
Christian Bollensdorff ◽  
Jassim Al Suwaidi ◽  
Magdi Yacoub
Keyword(s):  
Cardiac Hypertrophy ◽  
Critical Role ◽  
Calcium Entry ◽  
Store Operated Calcium Entry

Abstract 88: A Crucial Role of BAG3 in Preventing Dilated Cardiomyopathy

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Xi Fang ◽  
Julius Bogomolovas ◽  
Wei Zhang ◽  
Tongbin Wu ◽  
Canzhao Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Protein Quality ◽  
Contractile Function ◽  
Metabolic Stress ◽  
Insoluble Fraction ◽  
Therapeutic Benefit ◽  
Loss Of Function ◽  
Specific Subset

Defective protein quality control (PQC) systems are implicated in multiple diseases, with molecular chaperones/co-chaperones being critical to PQC. Cardiomyocytes are constantly challenged by mechanical and metabolic stress, placing great demand on the PQC system. Mutations and downregulation of the co-chaperone protein B cl-2- a ssociated athano g ene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to Dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and mechanisms by which the E455K mutation lead to DCM remained obscure. Here, we found that cardiac-specific BAG3 knockout (CKO) and cardiac-specific E455K BAG3 knockin mice developed DCM. Comparable phenotypes in the two mutants demonstrated that the E455K mutation resulted in loss-of-function, and experiments revealed that the E455K mutation disrupted interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a specific subset of proteins required for metabolic and contractile function of cardiomyocytes was enriched in the insoluble fraction. Together, these observations suggested that interaction between BAG3 and HSP70 was essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide new insight into the pathogenesis of heart failure caused by defects in BAG3 pathways, suggesting that increasing protein levels of BAG3 may be of therapeutic benefit in heart failure.

scholarly journals Maternal Exposure to High-Fat Diet Induces Long-Term Derepressive Chromatin Marks in the Heart

Nutrients ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 181 ◽  
Author(s):  
Guillaume Blin ◽  
Marjorie Liand ◽  
Claire Mauduit ◽  
Hassib Chehade ◽  
Mohamed Benahmed ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Heart Development ◽  
High Fat Diet ◽  
Target Genes ◽  
Critical Role ◽  
Maternal Exposure ◽  
High Fat ◽  
Cardiac Alterations

Heart diseases are a leading cause of death. While the link between early exposure to nutritional excess and heart disease risk is clear, the molecular mechanisms involved are poorly understood. In the developmental programming field, increasing evidence is pointing out the critical role of epigenetic mechanisms. Among them, polycomb repressive complex 2 (PRC2) and DNA methylation play a critical role in heart development and pathogenesis. In this context, we aimed at evaluating the role of these epigenetic marks in the long-term cardiac alterations induced by early dietary challenge. Using a model of rats exposed to maternal high-fat diet during gestation and lactation, we evaluated cardiac alterations at adulthood. Expression levels of PRC2 components, its histone marks di- and trimethylated histone H3 (H3K27me2/3), associated histone mark (ubiquitinated histone H2A, H2AK119ub1) and target genes were measured by Western blot. Global DNA methylation level and DNA methyl transferase 3B (DNMT3B) protein levels were measured. Maternal high-fat diet decreased H3K27me3, H2Ak119ub1 and DNA methylation levels, down-regulated the enhancer of zeste homolog 2 (EZH2), and DNMT3B expression. The levels of the target genes, isl lim homeobox 1 (Isl1), six homeobox 1 (Six1) and mads box transcription enhancer factor 2, polypeptide C (Mef2c), involved in cardiac pathogenesis were up regulated. Overall, our data suggest that the programming of cardiac alterations by maternal exposure to high-fat diet involves the derepression of pro-fibrotic and pro-hypertrophic genes through the induction of EZH2 and DNMT3B deficiency.

scholarly journals Metabolic reprogramming via PPARα signaling in cardiac hypertrophy and failure: From metabolomics to epigenetics

2017 ◽  
Vol 313 (3) ◽  
pp. H584-H596 ◽  
Author(s):  
Junco Shibayama Warren ◽  
Shin-ichi Oka ◽  
Daniela Zablocki ◽  
Junichi Sadoshima
Keyword(s):  
Cardiac Hypertrophy ◽  
Current Knowledge ◽  
Critical Role ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Global Changes ◽  
Peroxisome Proliferator ◽  
Metabolic Remodeling

Studies using omics-based approaches have advanced our knowledge of metabolic remodeling in cardiac hypertrophy and failure. Metabolomic analysis of the failing heart has revealed global changes in mitochondrial substrate metabolism. Peroxisome proliferator-activated receptor-α (PPARα) plays a critical role in synergistic regulation of cardiac metabolism through transcriptional control. Metabolic reprogramming via PPARα signaling in heart failure ultimately propagates into myocardial energetics. However, emerging evidence suggests that the expression level of PPARα per se does not always explain the energetic state in the heart. The transcriptional activities of PPARα are dynamic, yet highly coordinated. An additional level of complexity in the PPARα regulatory mechanism arises from its ability to interact with various partners, which ultimately determines the metabolic phenotype of the diseased heart. This review summarizes our current knowledge of the PPARα regulatory mechanisms in cardiac metabolism and the possible role of PPARα in epigenetic modifications in the diseased heart. In addition, we discuss how metabolomics can contribute to a better understanding of the role of PPARα in the progression of cardiac hypertrophy and failure.

scholarly journals Role of CyPA in cardiac hypertrophy and remodeling

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Mengfei Cao ◽  
Wei Yuan ◽  
Meiling Peng ◽  
Ziqi Mao ◽  
Qianru Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Interstitial Fibrosis ◽  
Systolic Function ◽  
Cardiac Fibroblasts ◽  
Cardiomyocyte Hypertrophy ◽  
Pathological Cardiac Hypertrophy ◽  
Complex Process

Abstract Pathological cardiac hypertrophy is a complex process and eventually develops into heart failure, in which the heart responds to various intrinsic or external stress, involving increased interstitial fibrosis, cell death and cardiac dysfunction. Studies have shown that oxidative stress is an important mechanism for this maladaptation. Cyclophilin A (CyPA) is a member of the cyclophilin (CyPs) family. Many cells secrete CyPA to the outside of the cells in response to oxidative stress. CyPA from blood vessels and the heart itself participate in a variety of signaling pathways to regulate the production of reactive oxygen species (ROS) and mediate inflammation, promote cardiomyocyte hypertrophy and proliferation of cardiac fibroblasts, stimulate endothelial injury and vascular smooth muscle hyperplasia, and promote the dissolution of extracellular matrix (ECM) by activating matrix metalloproteinases (MMPs). The events triggered by CyPA cause a decline of diastolic and systolic function and finally lead to the occurrence of heart failure. This article aims to introduce the role and mechanism of CyPA in cardiac hypertrophy and remodeling, and highlights its potential role as a disease biomarker and therapeutic target.

scholarly journals Investigating the role of super-enhancer RNAs underlying embryonic stem cell differentiation

BMC Genomics ◽  
2019 ◽  
Vol 20 (S10) ◽  
Author(s):  
Hao-Chun Chang ◽  
Hsuan-Cheng Huang ◽  
Hsueh-Fen Juan ◽  
Chia-Lang Hsu
Keyword(s):  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Heart Development ◽  
Critical Role ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Regulation Mechanism ◽  
Super Enhancer

Abstract Background Super-enhancer RNAs (seRNAs) are a kind of noncoding RNA transcribed from super-enhancer regions. The regulation mechanism and functional role of seRNAs are still unclear. Although super-enhancers play a critical role in the core transcriptional regulatory circuity of embryonic stem cell (ESC) differentiation, whether seRNAs have similar properties should be further investigated. Results We analyzed cap analysis gene expression sequencing (CAGE-seq) datasets collected during the differentiation of embryonic stem cells (ESCs) to cardiomyocytes to identify the seRNAs. A non-negative matrix factorization algorithm was applied to decompose the seRNA profiles and reveal two hidden stages during the ESC differentiation. We further identified 95 and 78 seRNAs associated with early- and late-stage ESC differentiation, respectively. We found that the binding sites of master regulators of ESC differentiation, including NANOG, FOXA2, and MYC, were significantly observed in the loci of the stage-specific seRNAs. Based on the investigation of genes coexpressed with seRNA, these stage-specific seRNAs might be involved in cardiac-related functions such as myofibril assembly and heart development and act in trans to regulate the co-expressed genes. Conclusions In this study, we used a computational approach to demonstrate the possible role of seRNAs during ESC differentiation.

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