scholarly journals Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Parveen Sharma ◽  
Cynthia Abbasi ◽  
Savo Lazic ◽  
Allen C. T. Teng ◽  
Dingyan Wang ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Cardiac Conduction ◽  
Intercalated Disc ◽  
Evolutionarily Conserved

Abstract 253: HSPB7 is Required for Maintaining the Intercalated Disc Structure to Prevent Cardiac Conduction System Failure in Mouse

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Wern-Chir Liao ◽  
Liang-Yi Juo ◽  
Yen-Hui Chen ◽  
Yu-Ting Yan
Keyword(s):  
Heart Failure ◽  
Gap Junction ◽  
Connexin 43 ◽  
Adherens Junction ◽  
Small Heat Shock Protein ◽  
Cardiac Conduction ◽  
Nucleotide Polymorphisms ◽  
Intercalated Disc ◽  
Junction Protein ◽  
And Function

HSPB7 is belonged to small heat-shock protein (HSPB) family and considered to function as a co-chaperone, which prevents protein aggregation and maintains protein structure. Single-nucleotide polymorphisms of HSPB7 associated with sporadic cardiomyopathy and heart failure have been identified in human patients. Additionally, HSPB7 is constitutively expressed in heart and rapidly increased in blood plasma after myocardial infarction, suggesting a functional role in the heart. In this study, we found that HSPB7 is highly colocalized with N-cadherin during the assembly and maturation of intercalated disc, suggesting that HSPB7 may involve in organizing and maintaining the cardiac cytoarchitecture. To elucidate the physiological function of HSPB7 in the adult heart, we generated a cardiac-specific inducible HSPB7 knockout mouse. Ablation of HSPB7 in the cardiomyocyte rapidly leads to heart failure, abnormal conduction properties and sudden arrhythmias death. Loss of HSPB7 did not cause significant changes in the organization of contractile proteins in sarcomeres, whereas severe abnormality in the intercalated disc was detected. The expression of connexin 43, a gap-junction protein located at the intercalated disc, was downregulated in HSPB7 knockout cardiomyocytes. Mislocalizations of desmoplakin (desmosomal proteins), and N-cadherin (adherens junction proteins) were also observed in the HSPB7 CKO hearts. Furthermore, filamin C, the interaction protein of HSPB7, was mislocalized and aggregated in HSPB7 mutant cardiomyocytes. The expressivity of the phenotype in the HSPB7 CKO mice is similar to human arrhythmogenic cardiomyopathy patients. Conclusively, we provide the first study characterizing HSPB7 as an intercalated disc protein. Our findings demonstrate that HSPB7 plays an essential role to maintain the structure and function of gap-junction complexes and intercalated disc and has vital implications for human heart disease.

scholarly journals Cardiomyocyte Expression of ZO-1 Is Essential for Normal Atrioventricular Conduction but Does Not Alter Ventricular Function

2020 ◽  
Vol 127 (2) ◽  
pp. 284-297 ◽  
Author(s):  
Jianlin Zhang ◽  
Kevin P. Vincent ◽  
Angela K. Peter ◽  
Matthew Klos ◽  
Hongqiang Cheng ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Optical Mapping ◽  
Physiological Role ◽  
Cardiac Conduction ◽  
Scaffolding Protein ◽  
Surface Ecg ◽  
Associated Proteins ◽  
And Function ◽  
Nodal Tissue ◽  
Intact Heart

Rationale: ZO-1 (Zonula occludens-1), a plasma membrane-associated scaffolding protein regulates signal transduction, transcription, and cellular communication. Global deletion of ZO-1 in the mouse is lethal by embryonic day 11.5. The function of ZO-1 in cardiac myocytes (CM) is largely unknown. Objective: To determine the function of CM ZO-1 in the intact heart, given its binding to other CM proteins that have been shown instrumental in normal cardiac conduction and function. Methods and Results: We generated ZO-1 CM-specific knockout (KO) mice using α-Myosin Heavy Chain-nuclear Cre (ZO-1cKO) and investigated physiological and electrophysiological function by echocardiography, surface ECG and conscious telemetry, intracardiac electrograms and pacing, and optical mapping studies. ZO-1cKO mice were viable, had normal Mendelian ratios, and had a normal lifespan. Ventricular morphometry and function were not significantly different between the ZO-1cKO versus control (CTL) mice, basally in young or aged mice, or even when hearts were subjected to hemodynamic loading. Atrial mass was increased in ZO-1cKO. Electrophysiological and optical mapping studies indicated high-grade atrioventricular (A-V) block in ZO-1cKO comparing to CTL hearts. While ZO-1-associated proteins such as vinculin, connexin 43, N-cadherin, and α-catenin showed no significant change with the loss of ZO-1, Connexin-45 and Coxsackie-adenovirus (CAR) proteins were reduced in atria of ZO-1cKO. Further, with loss of ZO-1, ZO-2 protein was increased significantly in ventricular CM in a presumed compensatory manner but was still not detected in the AV nodal myocytes. Importantly, the expression of the sodium channel protein NaV1.5 was altered in AV nodal cells of the ZO-1cKO versus CTL. Conclusions: ZO-1 protein has a unique physiological role in cardiac nodal tissue. This is in alignment with its known interaction with CAR and Cx45, and a new function in regulating the expression of NaV1.5 in AV node. Uniquely, ZO-1 is dispensable for function of the working myocardium.

scholarly journals Zebrafish Models in Therapeutic Research of Cardiac Conduction Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Rui Gao ◽  
Jie Ren
Keyword(s):  
Molecular Mechanisms ◽  
Atrioventricular Node ◽  
Conduction System ◽  
Cardiac Conduction ◽  
External Fertilization ◽  
Evolutionarily Conserved ◽  
Cardiovascular Defects ◽  
Vertebrate Model ◽  
Life Threatening ◽  
Therapeutic Research

Malfunction in the cardiac conduction system (CCS) due to congenital anomalies or diseases can cause cardiac conduction disease (CCD), which results in disturbances in cardiac rhythm, leading to syncope and even sudden cardiac death. Insights into development of the CCS components, including pacemaker cardiomyocytes (CMs), atrioventricular node (AVN) and the ventricular conduction system (VCS), can shed light on the pathological and molecular mechanisms underlying CCD, provide approaches for generating human pluripotent stem cell (hPSC)-derived CCS cells, and thus improve therapeutic treatment for such a potentially life-threatening disorder of the heart. However, the cellular and molecular mechanisms controlling CCS development remain elusive. The zebrafish has become a valuable vertebrate model to investigate early development of CCS components because of its unique features such as external fertilization, embryonic optical transparency and the ability to survive even with severe cardiovascular defects during development. In this review, we highlight how the zebrafish has been utilized to dissect the cellular and molecular mechanisms of CCS development, and how the evolutionarily conserved developmental mechanisms discovered in zebrafish could be applied to directing the creation of hPSC-derived CCS cells, therefore providing potential therapeutic strategies that may contribute to better treatment for CCD patients.

Remodeling the intercalated disc leads to cardiomyopathy in mice misexpressing cadherins in the heart

2002 ◽  
Vol 115 (8) ◽  
pp. 1623-1634 ◽  
Author(s):  
M. Celeste Ferreira-Cornwell ◽  
Yang Luo ◽  
Navneet Narula ◽  
Jennifer M. Lenox ◽  
Melanie Lieberman ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Transgenic Mice ◽  
Dilated Cardiomyopathy ◽  
Cyclin D1 ◽  
Connexin 43 ◽  
Ectopic Expression ◽  
Adherens Junction ◽  
Transgenic Animals ◽  
Intercalated Disc ◽  
E Cadherin

The contractile force of the cardiomyocyte is transmitted through the adherens junction, a component of the intercalated disc, enabling the myocardium to function as a syncytium. The cadherin family of cell adhesion receptors, located in the adherens junction, interact homophilically to mediate strong cell-cell adhesion. Ectopic expression of cadherins is associated with changes in tumor cell behavior and pathology. To examine the effect of cadherin specificity on cardiac structure and function, we expressed either the epithelial cadherin, E-cadherin, or N-cadherin in the heart of transgenic mice. E-cadherin was localized to the intercalated disc structure in these animals similar to endogenous N-cadherin. Both N- and E-cadherin transgenic animals developed dilated cardiomyopathy. However, misexpression of E-cadherin led to earlier onset and increased mortality compared with N-cadherin mice. A dramatic decrease in connexin 43 was associated with the hypertrophic response in E-cadherin transgenic mice. Myofibril organization appeared normal although, vinculin, which normally localizes to the intercalated disc, was redistributed to the cytoplasm in the E-cadherin transgenic mice. Furthermore, E-cadherin induced cyclin D1, nuclear reduplication, and karyokinesis in the absence of cytokinesis, resulting in myocytes with two closely opposed nuclei. By contrast, N-cadherin overexpressing transgenic mice did not exhibit an increase in cyclin D1,suggesting that E-cadherin may provide a specific growth signal to the myocyte. This study demonstrates that modulation of cadherin-mediated adhesion can lead to dilated cardiomyopathy and that E-cadherin can stimulate DNA replication in myocytes normally withdrawn from the cell cycle.

scholarly journals Microtubule cytoskeleton regulates Connexin 43 localization and cardiac conduction in cardiomyopathy caused by mutation in A-type lamins gene

2018 ◽  
Author(s):  
Coline Macquart ◽  
Rene Jüttner ◽  
Blanca Morales Rodriguez ◽  
Caroline Le Dour ◽  
Florence Lefebvre ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Cardiac Conduction ◽  
Microtubule Cytoskeleton

Abstract P361: Reduced Cardiac Tmem65 In Mouse Hearts Results In Intercalated Disc Defects And Eventual Dilated Cardiomyopathy With Cardiac Fibrosis

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Allen C Teng ◽  
Liyang Gu ◽  
Michelle Di Paola ◽  
Zachary Williams ◽  
Aaron Au ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Sodium Channel ◽  
Connexin 43 ◽  
Cardiac Fibrosis ◽  
Quantitative Polymerase Chain Reaction ◽  
Physical Interaction ◽  
Intercalated Disc ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated

The intercalated disc (ICD) is unique membrane structure that is indispensable to normal heart function. However, its structural organization is not well understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin 43 (Cx43) localization in cultured mouse neonatal cardiomyocytes. Here, we investigated the role of Tmem65 in ICD organization in vivo . A mouse model was established by injecting CD1 mouse pups (3-7 days after birth) with recombinant adeno-associated virus 9 (rAAV9) harboring Tmem65 (or scrambled) shRNA. Quantitative polymerase chain reaction (qPCR) and immunoblots confirmed greater than 85% reduction in Tmem65 expression (7.1±0.7% remained for Tmem65 proteins; 14.4±2.5% remained for Tmem65 transcripts, n =4) in mouse ventricles compared to control hearts. Tmem65 knockdown (KD) mice exhibited heart failure-like symptoms as early as 3 weeks post viral administration. Specifically, Tmem65 KD mice developed eccentric hypertrophic cardiomyopathy in 3 weeks and dilated cardiomyopathy with severe cardiac fibrosis in 7 weeks, as confirmed by H&E and Masson’s Trichrome staining. Echocardiography and electrocardiography, respectively, showed depressed hemodynamics (19.27±1.46ml/min for cardiac output in control hearts vs. 6.63±0.52ml/min for Tmem65 KD hearts, n =6) and impaired conduction, including prolonged PR (22.7±1.85ms in control hearts vs. 28.89±3.85ms in Tmem65 KD hearts, n≥8), QRS intervals (10.47±0.42ms in control hearts vs. 16.35±0.36ms in Tmem65 KD hearts, n≥8), and slowed heart rate (415±10bpm in control hearts vs. 347±16bpm in Tmem65 KD hearts, n≥8) in Tmem65 KD mouse hearts. Immunoprecipitation and super-resolution microscopy confirmed the physical interaction and localization between Tmem65 and voltage-gated sodium channel β subunit (β1) at the ICD and this interaction was evidently required for the establishment of perinexal nanodomains and voltage-gated sodium channel 1.5 (NaV1.5) localization to the ICD. Disrupting Tmem65 function, thus, impaired perinexal structure, reduced conduction velocity, and ultimately resulted in cardiomyopathy in vivo .

scholarly journals HSPB7 prevents cardiac conduction system defect through maintaining intercalated disc integrity

PLoS Genetics ◽  
2017 ◽  
Vol 13 (8) ◽  
pp. e1006984 ◽  
Author(s):  
Wern-Chir Liao ◽  
Liang-Yi Juo ◽  
Yen-Ling Shih ◽  
Yen-Hui Chen ◽  
Yu-Ting Yan
Keyword(s):  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Intercalated Disc ◽  
System Defect

Gap junctions–guards of excitability

2015 ◽  
Vol 43 (3) ◽  
pp. 508-512 ◽  
Author(s):  
Line Waring Stroemlund ◽  
Christa Funch Jensen ◽  
Klaus Qvortrup ◽  
Mario Delmar ◽  
Morten Schak Nielsen
Keyword(s):  
Sodium Channel ◽  
Crucial Role ◽  
Connexin 43 ◽  
Current Evidence ◽  
Intercalated Disc ◽  
Intercalated Discs ◽  
Cardiac Sodium Channel ◽  
Junctional Protein ◽  
Gap Junctional

Cardiomyocytes are connected by mechanical and electrical junctions located at the intercalated discs (IDs). Although these structures have long been known, it is becoming increasingly clear that their components interact. This review describes the involvement of the ID in electrical disturbances of the heart and focuses on the role of the gap junctional protein connexin 43 (Cx43). Current evidence shows that Cx43 plays a crucial role in organizing microtubules at the intercalated disc and thereby regulating the trafficking of the cardiac sodium channel NaV1.5 to the membrane.

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