EHD1 Modulates Cx43 Gap Junction Remodeling Associated With Cardiac Diseases

Martins‐Marques, Tânia; Catarino, Steve; Gonçalves, Alexandre; Miranda-Silva, Daniela; Gonçalves, Lino; Antunes, Pedro E.; Coutinho, Gonçalo F.; Moreira, Adelino Leite; Falcão-Pires, Inês; Girão, Henrique

doi:10.1161/circresaha.119.316502

Cited by 46 publications

(31 citation statements)

References 52 publications

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“…Cx43 PTMs, particularly phosphorylation of Cx43-S373 and Cx43-S368 and ubiquitination, have been associated with the control of GJ-mediated communication, namely, through modulation of protein–protein interactions associated with intracellular trafficking of Cx43 ( Smyth et al, 2014 ; Martins-Marques et al, 2020 ). Therefore, it is conceivable that phosphorylation and ubiquitination play also a regulatory role on the secretion of EV-Cx43.…”

Section: Resultsmentioning

confidence: 99%

“…WB analysis was performed as previously described ( Martins-Marques et al, 2020 ). For the analysis of CD63, CD81 or CD9, WB was performed in non-reducing conditions.…”

Section: Methodsmentioning

confidence: 99%

“…Cellular and EV lysates were prepared in radioimmunoprecipitation assay (RIPA) buffer, containing protease inhibitors ( Martins-Marques et al, 2020 ). IP of Cx43 was performed in 500 μg total protein lysates by incubation with 0.5 μg goat anti-Cx43 (AB0016; Sicgen) overnight, at 4°C under agitation.…”

Section: Methodsmentioning

confidence: 99%

“…The pathophysiology of acute myocardial infarction and consequent progression into chronic heart failure have been associated with altered trafficking of Cx43-containing GJs, many of these being correlated with changes in the phosphorylation and ubiquitination profile of Cx43 ( Fong et al, 2013 ; Smyth et al, 2014 ; Martins-Marques et al , 2015a , 2015b , 2015c, 2020 ; Ribeiro-Rodrigues et al, 2017b ). While the impact of ischemia on the modulation of GJ-mediated communication has been a matter of intense research, the consequences of ischemia-triggered events on the levels and/or function of EV-Cx43 channels remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes

et al. 2020

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Ischemic heart disease has been associated with an impairment on intercellular communication mediated by both gap junctions and extracellular vesicles. We have previously shown that connexin 43 (Cx43), the main ventricular gap junction protein, assembles into channels at the extracellular vesicle surface, mediating the release of vesicle content into target cells. Here, using a comprehensive strategy that included cell-based approaches, animal models and human patients, we demonstrate that myocardial ischemia impairs the secretion of Cx43 into circulating, intracardiac and cardiomyocyte-derived vesicles. In addition, we show that ubiquitin signals Cx43 release in basal conditions but appears to be dispensable during ischemia, suggesting an interplay between ischemia-induced Cx43 degradation and secretion. Overall, this study constitutes a step forward for the characterization of the signals and molecular players underlying vesicle protein sorting, with strong implications on long-range intercellular communication, paving the way towards the development of innovative diagnostic and therapeutic strategies for cardiovascular disorders.

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Section: Resultsmentioning

confidence: 99%

“…WB analysis was performed as previously described ( Martins-Marques et al, 2020 ). For the analysis of CD63, CD81 or CD9, WB was performed in non-reducing conditions.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes

et al. 2020

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“…More recently, it was reported that the lateralization of Cx43 in cardiomyocytes subjected to ischemia is mediated by Eps15 homology domain-containing protein 1 (EHD-1) via an endocytic recycling-like mechanism. Furthermore, it has been shown that EHD-1 drives the internalization of Cx43 through a process that requires phosphorylation at serine 368, ubiquitination of Cx43 and interaction with Eps15 [119]. Another relevant cardiac Cx43-interacting protein that was demonstrated to be involved in cardiac I/R injury is the ryanodine receptor 2 (RyR2), which is vital for proper cardiac contractility.…”

Section: Cx43 Protein Partners and Their Role In Cardiac I/r Injury-mmentioning

confidence: 99%

Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection

et al. 2020

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Since the mid-20th century, ischemic heart disease has been the world’s leading cause of death. Developing effective clinical cardioprotection strategies would make a significant impact in improving both quality of life and longevity in the worldwide population. Both ex vivo and in vivo animal models of cardiac ischemia/reperfusion (I/R) injury are robustly used in research. Connexin43 (Cx43), the predominant gap junction channel-forming protein in cardiomyocytes, has emerged as a cardioprotective target. Cx43 posttranslational modifications as well as cellular distribution are altered during cardiac reperfusion injury, inducing phosphorylation states and localization detrimental to maintaining intercellular communication and cardiac conduction. Pre- (before ischemia) and post- (after ischemia but before reperfusion) conditioning can abrogate this injury process, preserving Cx43 and reducing cell death. Pre-/post-conditioning has been shown to largely rely on the presence of Cx43, including mitochondrial Cx43, which is implicated to play a major role in pre-conditioning. Posttranslational modifications of Cx43 after injury alter the protein interactome, inducing negative protein cascades and altering protein trafficking, which then causes further damage post-I/R injury. Recently, several peptides based on the Cx43 sequence have been found to successfully diminish cardiac injury in pre-clinical studies.

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Ablation of Gap Junction Protein Improves the Efficiency of Nanozyme‐Mediated Catalytic/Starvation/Mild‐Temperature Photothermal Therapy

Dong

Akakuru

et al. 2023

Advanced Materials

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Reactive oxygen species (ROS)‐mediated tumor catalytic therapy is typically hindered by gap junction proteins that form cell‐to‐cell channels to remove cytotoxic ROS, thereby protecting tumor cells from oxidative damage. In this work, a multifunctional nanozyme, FePGOGA, is designed and prepared by Fe(III)‐mediated oxidative polymerization (FeP), followed by glucose oxidase (GOx) and GAP19 peptides co‐loading through electrostatic and π–π interactions. The FePGOGA nanozyme exhibits excellent cascade peroxidase‐ and glutathione‐oxidase‐like activities that efficiently catalyze hydrogen peroxide conversion to hydroxyl radicals and convert reduced glutathione to oxidized glutathione disulfide. The loaded GOx starves the tumors and aggravates tumor oxidative stress through glucose decomposition, while GAP19 peptides block the hemichannels by inducing degradation of Cx43, thus increasing the accumulation of intracellular ROS, and decreasing the transport of intracellular glucose. Furthermore, the ROS reacts with primary amines of heat shock proteins to destroy their structure and function, enabling tumor photothermal therapy at the widely sought‐after mild temperature (mildPTT, ≤45 °C). In vivo experiments demonstrate the significant antitumor effectof FePGOGA on cal27 xenograft tumors under near‐infrared light irradiation. This study demonstrates the successful ablation of gap junction proteins to overcome resistance to ROS‐mediated therapy, providing a regulator to suppress tumor self‐preservation during tumor starvation, catalytic therapy, and mildPTT.

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EHD1 Modulates Cx43 Gap Junction Remodeling Associated With Cardiac Diseases

Cited by 46 publications

References 52 publications

Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes

Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes

Canonical and Non-Canonical Roles of Connexin43 in Cardioprotection

Ablation of Gap Junction Protein Improves the Efficiency of Nanozyme‐Mediated Catalytic/Starvation/Mild‐Temperature Photothermal Therapy

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