EHD1 Modulates Cx43 Gap Junction Remodeling Associated With Cardiac Diseases

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 Connexin43 (Cx43). Although the molecular mechanisms remain unclear, altered distribution and function of GJ have been associated with acute myocardial infarction and heart failure (HF). Objective: A recent proteomic study from our laboratory identified Eps15 homology domain-containing protein 1 (EHD1) 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 GJ-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 GJ, paving the way to innovative therapeutic strategies aiming at preserving intercellular communication in the heart.