EHD1 Modulates Cx43 Gap Junction Remodeling Associated With Cardiac Diseases-Reference-Cited by-同舟云学术

EHD1 Modulates Cx43 Gap Junction Remodeling Associated With Cardiac Diseases

Published:2020-05-08 Issue:10 Volume:126 Page:
ISSN:0009-7330
Container-title:Circulation Research
language:en
Short-container-title:Circ Res

Author:

Martins-Marques Tania¹²³,Catarino Steve¹²³,Gonçalves Alexandre⁴,Miranda-Silva Daniela⁴,Gonçalves Lino³,Antunes Pedro¹³⁵,Coutinho Gonçalo¹³⁵,Leite Moreira Adelino⁴,Falcão Pires Inês⁴,Girão Henrique¹²³^ORCID

Affiliation:

1. From the Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine (T.M.-M., S.C., L.C., P.A., G.C., H.G.), University of Coimbra, Portugal

2. Center for Innovative Biomedicine and Biotechnology (T.M.-M., S.C., H.G.), University of Coimbra, Portugal

3. Clinical Academic Centre of Coimbra, CACC, Portugal (T.M-M., S.C., L.G., P.A., G.C., H.G.)

4. Department of Surgery and Physiology & Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Portugal (A.G., D.M.S., A.L.M., I.F.P.)

5. Cardiothoracic Surgery (P.A., G.C.), Coimbra Hospital and University Centre, Portugal.

Abstract

Rationale: Efficient communication between heart cells is vital to ensure the anisotropic propagation of electrical impulses, a function mainly accomplished by gap junctions (GJ) composed of Cx43 (connexin 43). Although the molecular mechanisms remain unclear, altered distribution and function of gap junctions have been associated with acute myocardial infarction and heart failure. Objective: A recent proteomic study from our laboratory identified EHD1 (Eps15 [endocytic adaptor epidermal growth factor receptor substrate 15] homology domain-containing protein 1) as a novel interactor of Cx43 in the heart. Methods and Results: In the present work, we demonstrate that knockdown of EHD1 impaired the internalization of Cx43, preserving gap junction-intercellular coupling in cardiomyocytes. Interaction of Cx43 with EHD1 was mediated by Eps15 and promoted by phosphorylation and ubiquitination of Cx43. Overexpression of wild-type EHD1 accelerated internalization of Cx43 and exacerbated ischemia-induced lateralization of Cx43 in isolated adult cardiomyocytes. In addition, we show that EHDs associate with Cx43 in human and murine failing hearts. Conclusions: Overall, we identified EHDs as novel regulators of endocytic trafficking of Cx43, participating in the pathological remodeling of gap junctions, paving the way to innovative therapeutic strategies aiming at preserving intercellular communication in the heart.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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