Dilated cardiomyopathy in Erb-b4-deficient ventricular muscle

2005 ◽  
Vol 289 (3) ◽  
pp. H1153-H1160 ◽  
Author(s):  
Hernán García-Rivello ◽  
Julián Taranda ◽  
Matilde Said ◽  
Patricia Cabeza-Meckert ◽  
Martin Vila-Petroff ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Receptor Tyrosine Kinase ◽  
Cardiac Development ◽  
Critical Role ◽  
Premature Death ◽  
Ventricular Muscle ◽  
Wild Type ◽  
Eccentric Hypertrophy ◽  
And Function ◽  
Intercellular Communications

The neuregulin receptor tyrosine kinase Erb-b4, initially linked to early cardiac development, is shown here to play a critical role in adult cardiac function. In wild-type mice, Erb-b4 protein localized to Z lines and to intercalated disks, suggesting a role in subcellular and intercellular communications of cardiomyocytes. Conditional inactivation of erb-b4 in ventricular muscle cells led to a severe dilated cardiomyopathy, characterized by thinned ventricular walls with eccentric hypertrophy, reduced contractility, and delayed conduction. This cardiac dysfunction may account for premature death in adult erb-b4-knockout mice. This study establishes a critical role for Erb-b4 in the maintenance of normal postnatal cardiac structure and function.

Abstract MP216: Identification Of Novel Phosphoprotein Signaling Pathways In Human Dilated Cardiomyopathy By Integrative Proteomic And Phosphoproteomic Analysis

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Cristine J Reitz ◽  
Marjan Tavassoli ◽  
Da Hye Kim ◽  
Sina Hadipour-Lakmehsari ◽  
Saumya Shah ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Tissue ◽  
Regulatory Element ◽  
Critical Role ◽  
Left Ventricular ◽  
Confocal Imaging ◽  
Intercalated Disc ◽  
Bioinformatics Analyses ◽  
Tissue Samples ◽  
And Function

Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure, yet the majority of the underlying signaling mechanisms remain poorly characterized. Protein phosphorylation is a key regulatory element with profound effects on the activity and function of signaling networks; however, there is a lack of comprehensive phosphoproteomic studies in human DCM patients. We assessed the hypothesis that an integrative phosphoproteomics analysis of human DCM would reveal novel phosphoprotein candidates involved in disease pathophysiology. Combined proteomic and phosphoproteomic analysis of explanted left ventricular tissue samples from DCM patients ( n =4) and non-failing controls ( n =4) identified 5,570 unique proteins with 13,624 corresponding phosphorylation sites. From these analyses, we identified αT-catenin as a unique candidate protein with a cluster of 4 significantly hyperphosphorylated sites in DCM hearts ( P <0.0001), with no change in total αT-catenin expression at the protein level. Bioinformatics analyses of human datasets and confocal imaging of human and mouse cardiac tissue show highly cardiac-enriched expression of αT-catenin, localized to the cardiomyocyte intercalated disc. High resolution 3-dimensional reconstruction shows elongated intercalated disc morphology in DCM hearts (10.07±0.76 μm in controls vs. 17.20±1.87 μm in DCM, P <0.05, n =3/group), with significantly increased colocalization of αT-catenin with the intercalated disc membrane protein N-cadherin (Pearson’s coefficient 0.55±0.04 in controls vs. 0.71±0.02 in DCM, P <0.05, n =3/group). To investigate the functional role of cardiac αT-catenin phosphorylation, we overexpressed WT protein vs. non-phosphorylatable forms based on the loci identified in DCM hearts, in adult mouse cardiomyocytes using lentiviral transduction. Confocal imaging revealed significant internalization of the phospho-null form, as compared to the prominent intercalated disc staining of the WT protein (17.78±0.79% of WT vs. 9.25±0.49% of 4A mutant, P <0.0001, n =50 cells/group). Together, these findings suggest a critical role for αT-catenin phosphorylation in maintaining cardiac intercalated disc organization in human DCM.

Cardiac expression of a gain-of-function α5-integrin results in perinatal lethality

2001 ◽  
Vol 280 (1) ◽  
pp. H361-H367 ◽  
Author(s):  
Maria L. Valencik ◽  
John A. McDonald
Keyword(s):  
Cardiac Development ◽  
Wild Type ◽  
Integrin Receptors ◽  
Gain Of Function ◽  
Transgenic Expression ◽  
Physiological Regulation ◽  
Myocyte Differentiation ◽  
Perinatal Lethality ◽  
And Function

Communication between the extracellular matrix and the intracellular signal transduction and cytoskeletal system is mediated by integrin receptors. α5β1-Integrin and its cognate ligand fibronectin are essential in development of mesodermal structures, myocyte differentiation, and normal cardiac development. To begin to explore the potential roles of α5β1-integrin specifically in cardiomyocytes, we used a transgenic expression strategy. We overexpressed two forms of the human α5-integrin in cardiomyocytes: the full-length wild-type α5-integrin and a putative gain-of-function mutation created by truncating the cytoplasmic domain, designated α5-1-integrin. Overexpression of the wild-type α5-integrin has no detectable adverse effects in the mouse, whereas expression of α5-1-integrin caused electrocardiographic abnormalities, fibrotic changes in the ventricle, and perinatal lethality. Thus physiological regulation of integrin function appears essential for maintenance of normal cardiomyocyte structure and function. This strengthens the role of inside-out signaling in regulation of integrins in vivo and suggests that integrins and associated signaling molecules are important in cardiomyocyte function.

scholarly journals Interactions between Brucella suis VirB8 and Its Homolog TraJ from the Plasmid pSB102 Underline the Dynamic Nature of Type IV Secretion Systems

2009 ◽  
Vol 191 (9) ◽  
pp. 2985-2992 ◽  
Author(s):  
Gisèle Bourg ◽  
Romain Sube ◽  
David O'Callaghan ◽  
Gilles Patey
Keyword(s):  
Critical Role ◽  
Type Iv Secretion ◽  
Dominant Negative Effect ◽  
Wild Type ◽  
Secretion Systems ◽  
Type Iv ◽  
Brucella Suis ◽  
Periplasmic Domain ◽  
Tm Domain ◽  
And Function

ABSTRACT The proteinVirB8 plays a critical role in the assembly and function of the Agrobacterium tumefaciens virB type IV secretion system (T4SS). The structure of the periplasmic domain of both A. tumefaciens and Brucella suis VirB8 has been determined, and site-directed mutagenesis has revealed amino acids involved in the dimerization of VirB8 and interactions with VirB4 and VirB10. We have shown previously that TraJ, the VirB8 homologue from pSB102, and the chimeric protein TraJB8, encompassing the cytoplasmic and transmembrane (TM) domains of TraJ and the periplasmic domain of VirB8, were unable to complement a B. suis mutant containing an in-frame deletion of the virB8 gene. This suggested that the presence of the TraJ cytoplasmic and TM domains could block VirB8 dimerization or assembly in the inner membrane. By bacterial two-hybrid analysis, we found that VirB8, TraJ, and the chimeras can all interact to form both homo- and heterodimers. However, the presence of the TM domain of TraJ resulted in much stronger interactions in both the homo- and heterodimers. We expressed the wild-type and chimeric proteins in wild-type B. suis. The presence of proteins carrying the TM domain of TraJ had a dominant negative effect, leading to complete loss of virulence. This suggests that the T4SS is a dynamic structure and that strong interactions block the spatial flexibility required for correct assembly and function.

Mutation of a conserved proline residue in the beta-subunit ectodomain prevents Na(+)-K(+)-ATPase oligomerization

1993 ◽  
Vol 265 (4) ◽  
pp. C1169-C1174 ◽  
Author(s):  
K. Geering ◽  
P. Jaunin ◽  
F. Jaisser ◽  
A. M. Merillat ◽  
J. D. Horisberger ◽  
...  
Keyword(s):  
Sodium Pump ◽  
Critical Role ◽  
Pump Current ◽  
Beta Subunit ◽  
Sequence Motif ◽  
Wild Type ◽  
Ouabain Binding ◽  
Conserved Sequence ◽  
External Potassium ◽  
And Function

A highly conserved sequence motif (4 tyrosines and 1 proline: YYPYY) of the Na(+)-K(+)-adenosinetriphosphatase (ATPase) beta 1-subunit ectodomain has been mutagenized to study its possible role in alpha/beta-assembly and sodium pump function. Single as well as double tyrosine mutants (tyrosine to phenylalanine: Y to F) of Xenopus laevis beta 1-subunits are able to associate with alpha 1-subunits and form functional Na-K pumps at the plasma membrane that are indistinguishable from wild-type alpha 1, beta 1-Na-K pumps (as assessed by measurements of ouabain binding, 86Rb flux, Na-K pump current, and activation by external potassium). In contrast, a single proline mutation (proline to glycine: P244G) reduced by > 90% the proper assembly and function of Na(+)-K(+)-ATPase, despite a normal rate of synthesis and core glycosylation. Our data indicate that proline-244 plays a critical role in the proper folding of the beta-subunit and its ability to associate efficiently with the alpha 1-subunit in the endoplasmic reticulum.

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.

scholarly journals The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation

2012 ◽  
Vol 302 (11) ◽  
pp. H2139-H2147 ◽  
Author(s):  
Brian Wadugu ◽  
Bernhard Kühn
Keyword(s):  
Heart Failure ◽  
Cardiac Development ◽  
Current Knowledge ◽  
Critical Role ◽  
Special Focus ◽  
Cardiomyocyte Proliferation ◽  
Neuregulin 1 ◽  
Adult Heart ◽  
Signaling Complex ◽  
And Function

The signaling complex consisting of the growth factor neuregulin-1 (NRG1) and its tyrosine kinase receptors ErbB2 and ErbB4 has a critical role in cardiac development and homeostasis of the structure and function of the adult heart. Recent research results suggest that targeting this signaling complex may provide a viable strategy for treating heart failure. Clinical trials are currently evaluating the effectiveness and safety of intravenous administration of recombinant NRG1 formulations in heart failure patients. Endogenous as well as administered NRG1 has multiple possible activities in the adult heart, but how these are related is unknown. It has recently been demonstrated that NRG1 administration can stimulate proliferation of cardiomyocytes, which may contribute to repair failing hearts. This review summarizes the current knowledge of how NRG1 and its receptors control cardiac physiology and biology, with special emphasis on its role in cardiomyocyte proliferation during myocardial growth and regeneration.

scholarly journals Regulation and Function of Syk Tyrosine Kinase in Mast Cell Signaling and Beyond

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Rodrigo Orlandini de Castro
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Conformational Changes ◽  
Protein Tyrosine Kinase ◽  
Critical Role ◽  
Wild Type ◽  
And Function

The protein tyrosine kinase Syk plays a critical role in FcεRI signaling in mast cells. Binding of Syk to phosphorylated immunoreceptor tyrosine-based activation motifs (p-ITAM) of the receptor subunits results in conformational changes and tyrosine phosphorylation at multiple sites that leads to activation of Syk. The phosphorylated tyrosines throughout the molecule play an important role in the regulation of Syk-mediated signaling. Reconstitution of receptor-mediated signaling in Syk-/- cells by wild-type Syk or mutants which have substitution of these tyrosines with phenylalanine together with in vitro assays has been useful strategies to understand the regulation and function of Syk.

Myocardial extra-cellular matrix and its regulation by metalloproteinases and their inhibitors

2005 ◽  
Vol 93 (02) ◽  
pp. 212-219 ◽  
Author(s):  
Zamaneh Kassiri ◽  
Rama Khokha
Keyword(s):  
Heart Failure ◽  
Cardiac Development ◽  
Critical Role ◽  
Left Ventricular ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Western World ◽  
A Disintegrin And Metalloproteinase ◽  
And Function ◽  
Myocardial Injuries

SummaryCardiovascular disease poses a major health care burden in the Western world. Following myocardial injuries, ventricular remodelling and dysfunction ensue, which can eventually culminate in heart failure. An important event in left ventricular (LV) remodelling is alteration of the extracellular matrix (ECM) integrity, the structural network that interconnects the myocardial components. The critical role of ECM remodelling in cardiac dilation and heart failure was recognized more than a decade ago, and the molecular factors responsible for this process are now being explored. Abnormal ECM turnover is primarily brought about by an imbalance in the activity of matrix metalloproteinases (MMPs) that degrade ECM components, and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Here we provide an overview of composition of the cardiac ECM, and alterations in ECM regulatory proteins, MMPs and TIMPs, in human heart disease. We also discuss the role of TIMPs, MMPs, and a disintegrin and metalloproteinase (ADAMs) enzymes in cardiac development and function as learned through genetically altered mouse models.

Flt3-Ligand Plays a Critical Role in Development and Function of CD8+/TCR− Facilitating Cells in Bone Marrow,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4003-4003
Author(s):  
Yiming Huang ◽  
Thomas Miller ◽  
Hong Xu ◽  
Yujie Wen ◽  
Suzanne T Ildstad
Keyword(s):  
Bone Marrow ◽  
Critical Role ◽  
Flt3 Ligand ◽  
Wild Type ◽  
Graft Versus Host ◽  
Equity Ownership ◽  
Total Body ◽  
And Function

Abstract Abstract 4003 Graft facilitating cells (FC) are a CD8+/TCR− bone marrow subpopulation that enhance engraftment of purified hematopoietic cells (HSC) in allogeneic mouse recipients without causing graft-versus-host disease. They also enhance engraftment of suboptimal numbers of syngeneic HSC. FC induce antigen-specific CD4+/CD25+/FoxP3+ regulatory T cells in vivo. The major subpopulation in FC is resembles plasmacytoid precursor dendritic cells (p-preDC) both phenotypically and functionally. Treatment of mice with Flt3 ligand (FL) results in a significant increase in FC in peripheral blood (PB) and FL-expanded-PB FC enhanced HSC engraftment. In this study, we evaluated the role of FL in FC development using FL-KO mice. We first compared FC from FL-KO B6 mice with FC from B6 mice to evaluate the FC total cellular composition. The number of FC was significantly decreased in FL-KO mice compared to wild type controls (P = 0.0003). The number of p-preDC FC was also significantly decreased (P = 0.0001), suggesting that FL is important in the development of p-preDC FC. Next, we tested whether FL-KO FC facilitate engraftment of HSC in allogeneic recipients. FC were sorted from FL-KO B6 mice and HSC (C-Kit+/Sca-1+/Lin−) were sorted from B6 mice. 10,000 B6 HSC plus 30,000 FL-KO FC were transplanted into NOD recipients conditioned with 950 cGy of total body irradiation. Controls received 10,000 B6 HSC with or without 30,000 B6 FC. Only 36% (5 of 14) NOD recipients of B6 HSC alone engrafted and two mice survived up to 160 days (Figure). Sixty-three percent (5 of 8) of recipients transplanted with B6 HSC + FL-KO B6 FC engrafted and only one mouse survived up to 160 days. Seventy-five percent (9 of 12) recipients of B6 HSC + B6 FC engrafted and seven of the mice survived more than 160 days. The level of donor chimerism in recipients of B6 HSC + B6 FC (57% ± 10%) was significantly higher than recipients of B6 HSC + FL-KO B6 FC (14% ± 3%; P = 0.003) or B6 HSC alone (22% ± 6%; P = 0.005). These data demonstrate that FL-KO FC fail to facilitate durable allogeneic HSC engraftment, suggesting that flt3-ligand plays a critical role in development of functional FC. Disclosures: Ildstad: Regenerex, LLC: Equity Ownership.

Abstract 390: Dysregulation of ATF2 in Dilated Cardiomyopathy Caused by FBXO32 Mutation

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Nadya Alyacoub ◽  
Salma Awad ◽  
Mohmad Kunhi ◽  
Walid Al-Habeeb ◽  
Coralie Poizat
Keyword(s):  
Transcription Factor ◽  
Dilated Cardiomyopathy ◽  
Leucine Zipper ◽  
Novel Mutation ◽  
Systolic Dysfunction ◽  
Critical Role ◽  
Neonatal Rat ◽  
Wild Type ◽  
Rat Cardiomyocytes ◽  
Scf Complex

Background: Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy causing systolic dysfunction and heart failure. Rare variants in more than 30 genes mostly encoding sarcomeric proteins and proteins of the extracellular matrix have been implicated in familial DCM to date. We recently identified a novel mutation (Gly243Arg) in FBXO32 causing familial DCM through abnormal SKP1/CUL/F-BOX (SCF) complex formation and defects in proteins regulating the autophagy/lysosome machinery (Al-Yacoub, Genome Biology, 2016). Objective: To explore in more details the mechanisms by which the defective SCF FBXO32 complex leads to the development of DCM. Methodology: Using a PCR-based microarray, we screened for mRNAs significantly dysregulated in the heart of the patient carrying the FBXO32 mutation compared to control and idiopathic human hearts. Subsequently, we validated dysregulation of a candidate gene using immunoblot analysis and tested the effect of the mutant or wild-type FBXO32 on the novel candidate identified in primary neonatal rat cardiomyocytes. Results: We found a robust up-regulation in mRNA expression of the Activating transcription Factor 2 (ATF2), a member of the leucine zipper family of DNA binding proteins, which plays a critical role in cardiac development. ATF2 protein level was also strongly increased in the heart with the FBXO32 mutation compared to control hearts and to hearts of idiopathic origin. Expression of the mutant FBXO32 protein in primary cardiomyocytes enhanced ATF2 protein expression compared to cells expressing the wild-type FBXO32 protein. Since FBXO32 is member of the SCF complex and has ubiquitin ligase activity, experiments are now investigating whether FBXO32 directly regulates ATF2 protein stability and the role of ATF2 in autophagy flux regulation in dilated cardiomyopathy. Conclusion: Our results indicate that abnormal SCF activity due to the FBXO32 mutation stabilizes the AFT2 transcription factor and suggest a new mechanism by aberrant SCF activity causes DCM in human.

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