Abstract
To clarify the precise mechanism for the progression of advanced heart failure (AdHF), we assessed the scheme in two HF models, using (I) TO-2 strain hamsters sharing common genetic and clinical features to human families with the δ-sarcoglycan (SG) gene mutation and (II) administration of a high-dose (HD) of isoproterenol (Isp) to normal rats. δ-SG is a component in dystrophin (Dys)-related proteins that stabilize the sarcolemma (SL) during repeated heart beats. In TO-2, we followed time course of hemodynamics, immunostaining and Western blotting of Dys and in situ SL permeability by Evans blue uptake with or without the gene therapy. Dys was age-dependently translocated from the SL to myoplasm (MP) where the SL instability accompanied the fragmention of Dys. By gene therapy to supplement the normal δ-SG gene in hearts in vivo, we found that Dys translocation was selectively improved in cardiomyocytes expressing the δ-SG transgene, where the SL fragility was ameliorated. Most importantly, the survival period of the animals was prolonged. Furthermore, Dys but not δ-SG was also time-dependently shifted with a HD of Isp from the SL to MP and fragmented, while δ-SG was preserved intact. We present a novel paradigm that disruption of Dys, but not δ-SG per se, leads to AdHF irrespective of hereditary or acquired origin.
