RATIONALE: Hydroxymethyl glutaryl-coenzyme A reductase degradation protein 1 
(Hrd1) is an endoplasmic reticulum (ER)-transmembrane E3 ubiquitin ligase that 
has been studied in yeast, where it contributes to ER protein quality control by 
ER-associated degradation (ERAD) of misfolded proteins that accumulate during ER 
stress. Neither Hrd1 nor ERAD has been studied in the heart, or in cardiac 
myocytes, where protein quality control is critical for proper heart function.
OBJECTIVE: The objective of this study were to elucidate roles for Hrd1 in ER 
stress, ERAD, and viability in cultured cardiac myocytes and in the mouse heart, 
in vivo.
METHODS AND RESULTS: The effects of small interfering RNA-mediated Hrd1 
knockdown were examined in cultured neonatal rat ventricular myocytes. The 
effects of adeno-associated virus-mediated Hrd1 knockdown and overexpression 
were examined in the hearts of mice subjected to pressure overload-induced 
pathological cardiac hypertrophy, which challenges protein-folding capacity. In 
cardiac myocytes, the ER stressors, thapsigargin and tunicamycin increased ERAD, 
as well as adaptive ER stress proteins, and minimally affected cell death. 
However, when Hrd1 was knocked down, thapsigargin and tunicamycin dramatically 
decreased ERAD, while increasing maladaptive ER stress proteins and cell death. 
In vivo, Hrd1 knockdown exacerbated cardiac dysfunction and increased apoptosis 
and cardiac hypertrophy, whereas Hrd1 overexpression preserved cardiac function 
and decreased apoptosis and attenuated cardiac hypertrophy in the hearts of mice 
subjected to pressure overload.
CONCLUSIONS: Hrd1 and ERAD are essential components of the adaptive ER stress 
response in cardiac myocytes. Hrd1 contributes to preserving heart structure and 
function in a mouse model of pathological cardiac hypertrophy.