Abstract

An Arg9 to Cys point mutation in phospholamban (PLN) is the leading cause of dilated cardiomyopathy (DCM) in both humans and in transgenic mice (TgPLNR9C mice). Our earlier study of PLN showed that impaired autophagic flux in HECT domain and Ankyrin repeat‐containing E3 ubiquitin protein ligase 1 (HACE1)‐null mouse hearts was associated with increased PLN protein levels. Here, we show that HACE1 expression was decreased in 8‐, 16‐weeks old TgPLNR9C mouse hearts, and PLN was co‐immunoprecipitated with the autophagic adapter protein, p62, and confocal immunofluorescent microscopy revealed intracellular co‐localization of PLN with p62. At the same time, electron microscopy showed increased autophagosome in TgPLNR9C mouse hearts. These results suggest that PLN is degraded by autophagy, and an impairment of the autophagy pathway promotes PLN accumulation in TgPLNR9C mouse hearts. Furthermore, we also observed decreased expression of the von Hippel‐Lindau (VHL), another E3 ubiquitin ligase in TgPLNR9C mouse hearts. Taken together, we propose that diminished expression of E3 ubiquitin ligases, such as HACE1 and VHL could be related to the progression to DCM in TgPLNR9C mice.

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