Abstract
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.
Highlights
Intercellular communication in the heart can either occur directly, via connexin 43 (Cx43)–containing gap junctions (GJs), or at longer distances, through soluble factors and extracellular vesicles (EVs) (Ribeiro-Rodrigues et al, 2017b; Sluijter et al, 2018; Martins-Marques et al, 2019)
The presence of Cx43 in EVs isolated from cultured cells and peripheral blood has been reported, the impact of ischemia-triggered events on EV-Cx43 sorting remains obscure (Soares et al, 2015; MartinsMarques et al, 2016)
Because the content of released EVs can mirror the pathophysiological state of cells, particular clinical relevance has been attributed to circulating EVs, which may serve as potential disease biomarkers
Summary
Intercellular communication in the heart can either occur directly, via connexin 43 (Cx43)–containing gap junctions (GJs), or at longer distances, through soluble factors and extracellular vesicles (EVs) (Ribeiro-Rodrigues et al, 2017b; Sluijter et al, 2018; Martins-Marques et al, 2019). EV secretion is preceded by the formation of multivesicular bodies (MVBs) that upon fusion with the plasma membrane, release its intraluminal vesicles (ILVs) into the extracellular space. These mechanisms are shared with those implicated in the degradative MVB–lysosome pathway, involving recognition of ubiquitinated cargo by the endosomal sorting complexes required for transport (ESCRT) machinery, including tumor suppressor gene 101 (Tsg101) and hepatocyte growth factor– regulated tyrosine kinase substrate (Hrs) (van Niel et al, 2011; Colombo et al, 2013). What distinguishes secretory from degradative MVBs is currently unknown
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