Introduction:
Cardiac hypertrophy is associated with an increase in protein synthesis, which must coordinate with protein folding and degradation to allow for homeostatic growth without affecting the functional integrity of cardiac myocytes (i.e. proteostasis). There is a
gap in our understanding
of how proteostasis becomes imbalanced during chronic pathological hypertrophy.
Hypothesis:
The
objective
of this study to examine the mechanisms regulating the protein degradation aspect of proteostasis, ER associated degradation (ERAD), by focusing on the role in cardiac hypertrophy of the unique selenoprotein and functional initiator of the ERAD molecular machinery, VIMP, which is induced in cardiac pathology by the nodal proteostasis transcription factor, ATF6.
Methods and Results:
VIMP was increased in failing human and in mouse hearts subjected to TAC-induced heart failure in an ATF6-dependent manner. AAV9-shRNA-mediated VIMP knockdown in the heart dramatically suppressed cardiac hypertrophy and staved off decompensation and heart failure, while AAV9-mediated VIMP overexpression exacerbated cardiac decompensation in response to TAC, an effect not observed with overexpression of an ERAD-null mutant of VIMP. Unexpectedly, VIMP knockdown enhanced ERAD-mediated degradation of the cytosolic pro-hypertrophic kinase, serum/glucocorticoid-regulated kinase 1, SGK1. Furthermore, AAV9-mediated overexpression of SGK1 negated the beneficial effects of VIMP knockdown; knockdown of the SGK1-binding protein, GILZ enhanced ERAD-mediated degradation of SGK1 and blunted cardiac hypertrophy. A peptide inhibiting the SGK1-GILZ interaction enhanced the ERAD-mediated degradation of SGK1 and ameliorated agonist-induced cardiac myocyte hypertrophy.
Conclusions:
Here we studied ERAD for the first time in any organ,
in vivo
, finding that an ATF6-inducible selenoprotein, VIMP, regulates the ERAD-dependent degradation of SGK1, thus accelerating TAC-induced cardiac decompensation and heart failure.