心筋ジストロフィンの細胞内移行と断片化による心不全一般の重症化機構と、その新たな治療戦略
詳細
The progression mechanism from cardiac dysfunction to advanced heart failure (HF) including dilated cardiomyopathy (DCM) should be clarified to establish a novel treatment. We have identified a gene mutation in δ-sarcoglycan (SG) that causes hereditary DCM in both animals (Sakamoto et al., PNAS, 1997) and humans (Tsubata et al., JCI, 2000). TO-2 hamsters with hereditary DCM show age-dependent cleavage and translocation of myocardial dystrophin (Dys) from sarcolemma (SL) to myoplasm, enhanced SL permeability in situ, and a close relation between Dys loss and hemodynamics. Dys disruption is not an epiphenomenon but directly causes advanced HF, because in vivo transfer of the missing gene to degrading cardiomyocytes ameliorated all of the pathological features and improved the disease prognosis (Kawada et al., PNAS, 2002). Furthermore, acute HF after isoproterenol toxicity and chronic HF after coronary ligation in rats both time-dependently cause Dys disruption in the degrading myocardium (Takahashi et al., CVRes., 2005). Dys cleavage was also detected in human hearts from patients with DCM of unidentified etiology, supporting a scheme of vicious cycle consisting of SL instability, Dys cleavage, and translocation of Dys from the SL to the myoplasm (Toyo-oka et al., PNAS, 2004), irrespective of an acute or chronic process and a hereditary or acquired origin. Activation of endogenous calpain will be discussed for the Dys disruption. [J Physiol Sci. 2006;56 Suppl:S53]
