Ischemia-induced autophagy leads to degradation of gap junction protein Connexin43 in cardiomyocytes

Gap junction intercellular communication (GJIC) between cardiomyocytes is essential for synchronous heart contraction and relies on Connexin (Cx)-containing channels. Increased breakdown of Cx43 has been often associated with various cardiac diseases. However, the mechanisms whereby Cx43 is degraded in ischemic heart remain unknown. The results obtained in this study, using both HL-1 cells and organotypic heart cultures, show that simulated ischemia induces degradation of Cx43 that can be prevented by chemical or genetic inhibitors of autophagy. Additionally, ischemia-induced degradation of Cx43 results in GJIC impairment in HL-1 cells, which can be restored by autophagy inhibition. In cardiomyocytes, ubiquitin signals Cx43 for autophagic degradation, through the recruitment of the ubiquitin-binding proteins Eps15 and p62, that assist in Cx43 internalization and targeting to autophagic vesicles, via LC3. Moreover, we establish that degradation of Cx43 in ischemia or ischemia/reperfusion (I/R) relies upon different molecular players. Indeed, degradation of Cx43 during early periods of ischemia depends on AMPK, whereas in late periods of ischemia and I/R requires Beclin 1. In the Langendorff-perfused heart, Cx43 is dephosphorylated in ischemia and degraded during I/R, where Cx43 degradation correlates with autophagy activation. In summary, the results of this study provide new evidence regarding the molecular mechanisms whereby Cx43 is degraded in ischemia, which may contribute...

Source: BJ Cell - January 21, 2015 Category: Biochemistry Authors: T Martins-Marques, S Catarino, M Zuzarte, C Marques, P Matafome, P Pereira, H Girão Tags: BJ Cell Source Type: research