scholarly journals Conserved cysteines in titin sustain the mechanical function of cardiomyocytes

2020 ◽  
Author(s):  
Elías Herrero-Galán ◽  
Fernando Domínguez ◽  
Inés Martínez-Martín ◽  
Cristina Sánchez-González ◽  
Natalia Vicente ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
High Frequency ◽  
Functional Annotation ◽  
Contractile Function ◽  
Missense Mutations ◽  
Mechanical Function ◽  
Direct Impact ◽  
Functional Studies ◽  
Uncertain Significance

AbstractThe protein titin determines cardiomyocyte contraction and truncating variants in the titin gene (TTN) are the most common cause of dilated cardiomyopathy (DCM). Different to truncations, missense variants in TTN are currently classified as variants of uncertain significance due to their high frequency in the population and the absence of functional annotation. Here, we report the regulatory role of conserved, mechanically active titin cysteines, which, contrary to current views, we uncover to be reversibly oxidized in basal conditions leading to isoform- and force-dependent modulation of titin stiffness and dynamics. Building on our functional studies, we demonstrate that missense mutations targeting a conserved titin cysteine alter myocyte contractile function and cause DCM in humans. Our findings have a direct impact on genetic counselling in clinical practice.One sentence summaryMutations targeting cysteines key to the mechanoredox control of titin cause human dilated cardiomyopathy

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 Role of Cardiac Magnetic Resonance in the Evaluation of Dilated Cardiomyopathy: Diagnostic Contribution and Prognostic Significance

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
Marco Francone
Keyword(s):  
Dilated Cardiomyopathy ◽  
Prognostic Significance ◽  
Therapeutic Strategies ◽  
Present Condition ◽  
Individual Risk ◽  
Disease Monitoring ◽  
Mechanical Function ◽  
Pathological Conditions ◽  
Technological Developments

Dilated cardiomyopathy (DCM) represents the final common morphofunctional pathway of various pathological conditions in which a combination of myocyte injury and necrosis associated with tissue fibrosis results in impaired mechanical function. Recognition of the underlying aetiology of disease and accurate disease monitoring may be crucial to individually optimize therapeutic strategies and stratify patient’s prognosis. In this regard, CMR has emerged as a new reference gold standard providing important information for differential diagnosis and new insight about individual risk stratification. The present review article will focus on the role of CMR in the evaluation of present condition, analysing respective strengths and limitations in the light of current literature and technological developments.

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.

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

Ionic homeostasis and subcellular element compartmentation

1990 ◽  
Vol 48 (2) ◽  
pp. 150-151
Author(s):  
Ann LeFurgey ◽  
Peter Ingram ◽  
J.J. Blum ◽  
M.C. Carney ◽  
L.A. Hawkey ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Ionic Homeostasis ◽  
X Ray ◽  
Functional Studies ◽  
Cell Compartments ◽  
X Ray Imaging ◽  
Resolution Electron ◽  
Multiple Cell ◽  
Role Of Zn

Subcellular compartments commonly identified and analyzed by high resolution electron probe x-ray microanalysis (EPXMA) include mitochondria, cytoplasm and endoplasmic or sarcoplasmic reticulum. These organelles and cell regions are of primary importance in regulation of cell ionic homeostasis. Correlative structural-functional studies, based on the static probe method of EPXMA combined with biochemical and electrophysiological techniques, have focused on the role of these organelles, for example, in maintaining cell calcium homeostasis or in control of excitation-contraction coupling. New methods of real time quantitative x-ray imaging permit simultaneous examination of multiple cell compartments, especially those areas for which both membrane transport properties and element content are less well defined, e.g. nuclei including euchromatin and heterochromatin, lysosomes, mucous granules, storage vacuoles, microvilli. Investigations currently in progress have examined the role of Zn-containing polyphosphate vacuoles in the metabolism of Leishmania major, the distribution of Na, K, S and other elements during anoxia in kidney cell nuclel and lysosomes; the content and distribution of S and Ca in mucous granules of cystic fibrosis (CF) nasal epithelia; the uptake of cationic probes by mltochondria in cultured heart ceils; and the junctional sarcoplasmic retlculum (JSR) in frog skeletal muscle.

The role of dyslipidemia in idiopathic dilated cardiomyopathy

2008 ◽  
Vol 7 ◽  
pp. 29-29
Author(s):  
M SKWAREK ◽  
Z BILINSKA ◽  
L MAZURKIEWICZ ◽  
J GRZYBOWSKI ◽  
M KRUK ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Idiopathic Dilated Cardiomyopathy

Anti-Myelin Oligodendrocyte Glycoprotein Encephalomyelitis and Extensive Longitudinal Transverse Myelitis Associated with Compound Heterozygous NLRP3 Missense Mutations in a Young Child

2020 ◽  
Author(s):  
Deirdre O'Sullivan ◽  
Michael Moore ◽  
Susan Byrne ◽  
Andreas O. Reiff ◽  
Susanna Felsenstein
Keyword(s):  
Young Child ◽  
Genetic Basis ◽  
Transverse Myelitis ◽  
Acute Disseminated Encephalomyelitis ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Childhood Onset

AbstractAcute disseminated encephalomyelitis in association with extensive longitudinal transverse myelitis is reported in a young child with positive anti-myelin oligodendrocyte glycoprotein (MOG) antibody with heterozygous NLRP3 missense mutations; p.(Arg488Lys) and p.(Ser159Ile). This case may well present an exceptional coincidence, but may describe a yet unrecognized feature of the spectrum of childhood onset cryopyrinopathies that contribute to the understanding of the genetic basis for anti-MOG antibody positive encephalomyelitis. Based on this observation, a larger scale study investigating the role of NLRP3 and other inflammasomes in this entity would provide important pathophysiological insights and potentially novel avenues for treatment.

Identification of new ARMC5 missense mutations in Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) and their functional studies in vitro

2018 ◽  
Author(s):  
Anna Vaczlavik ◽  
Stephanie Espiard ◽  
Marie-Odile North ◽  
Ludivine Drougat ◽  
Marthe Rizk-Rabin ◽  
...  
Keyword(s):  
Missense Mutations ◽  
Adrenal Hyperplasia ◽  
Functional Studies

Calculation-and-experimental estimation of the role of the frequency ratio in changing the endurance at two-frequency deformation modes

2019 ◽  
Vol 85 (1(I)) ◽  
pp. 64-71 ◽  
Author(s):  
M. M. Gadenin
Keyword(s):  
High Frequency ◽  
Experimental Studies ◽  
Low Frequency ◽  
Reduction Factor ◽  
Single Frequency ◽  
Cyclic Loads ◽  
Small Ratio ◽  
Harmonic Components ◽  
Deformation Modes

The cycle configuration at two-frequency loading regimes depends on the number of parameters including the absolute values of the frequencies and amplitudes of the low-frequency and high-frequency loads added during this mode, the ratio of their frequencies and amplitudes, as well as the phase shift between these harmonic components, the latter having a significant effect only with a small ratio of frequencies. Presence of such two-frequency regimes or service loading conditions for parts of machines and structures schematized by them can significantly reduce their endurance. Using the results of experimental studies of changes in the endurance of a two-frequency loading of specimens of cyclically stable, cyclically softened and cyclically hardened steels under rigid conditions we have shown that decrease in the endurance under the aforementioned conditions depends on the ratio of frequencies and amplitudes of operation low-frequency low-cycle and high-frequency vibration stresses, and, moreover, the higher the level of the ratios of amplitudes and frequencies of those stacked harmonic processes of loading the greater the effect. It is shown that estimation of such a decrease in the endurance compared to a single frequency loading equal in the total stress (strains) amplitudes can be carried out using an exponential expression coupling those endurances through a parameter (reduction factor) containing the ratio of frequencies and amplitudes of operation cyclic loads and characteristic of the material. The reduction is illustrated by a set of calculation-experimental curves on the corresponding diagrams for each of the considered types of materials and compared with the experimental data.

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