Abstract 5899: Chronic Proteasome Inhibition Leads to Dilative Cardiomyopathy
Background: The proteasome is responsible for the degradation of the majority of proteins in eukaryotic cells, especially those that are damaged and/or misfolded. Hence, the proteasome is an important component of intracellular protein quality mechanisms. The significance of this proteolytic complex for cardiac function, however, remains to be determined.
Methods: Female domestic pigs, 3 months of age, were randomized to a normal diet (N, n=6) or HC (daily dietary load of 2% cholesterol, 15% lard, n=6) without or with twice weekly subcutaneous injections of the proteasome inhibitor MLN-273 (0.08 mg/kg, HC+PSI, n=5). In vivo data on cardiac dimensions and function was obtained by EBCT after 11 weeks. Ex vivo tissue analyses were performed on hearts harvested after 12 weeks and included TUNEL staining for the determination of the apoptotic index (TUNEL+ cells per myocardial area) and immunoblotting for the expression of pro-apoptotic factors such as caspase 12.
Results: These are as listed in Table 1⇓.
Conclusions: Chronic proteasome inhibition leads to dilative cardiomyopathy along with an increase in apoptotic cells in the myocardium and stimulation of the caspase-12 proapoptotic pathways, possibly indicating induction of endoplasmic reticulum stress as the underlying pathophysiological mechanism. The current study supports a role for the proteasome in the regulation of cardiac structure and function.