A novel scheme of dystrophin disruption for the progression of advanced heart failure.
The precise mechanism of the progression of advanced heart failure is unknown. We assessed a new scheme in two heart failure models: (I) congenital dilated cardiomyopathy (DCM) in TO-2 strain hamsters lacking delta-sarcoglycan (SG) gene and (II) administration of a high-dose of isoproterenol, as an acute heart failure in normal rats. In TO-2 hamsters, we followed the time course of the histological, physiological and metabolic the progressions of heart failure to the end stage. Dystrophin localization detected by immunostaining age-dependently to the myoplasm and the in situ sarcolemma fragility evaluated by Evans blue entry was increased in the same cardiomyocytes. Western blotting revealed a limited cleavage of the dystrophin protein at the rod domain, strongly suggesting a contribution of endogenous protease(s). We found a remarkable up-regulation of the amount of calpain-1 and -2, and no change of their counterpart, calpastatin. After supplementing TO-2 hearts with the normal delta-SG gene in vivo, these pathological alterations and the animals' survival improved. Furthermore, dystrophin but not delta-SG was disrupted by a high dose of isoproterenol, translocated from the sarcolemma to the myoplasm and fragmented. These results of heart failure, irrespective of the hereditary or acquired origin, indicate a vicious cycle formed by the increased sarcolemma permeability, preferential activation of calpain over calpastatin, and translocation and cleavage of dystrophin would commonly lead to advanced heart failure.
Kawada
Tomie
T
Division of Pharmacy, Niigata University of Medical and Dental Hospital, Niigata, 951-8520, Japan.
Masui
Fujiko
F
Tezuka
Asaki
A
Ebisawa
Takashi
T
Kumagai
Hiroyuki
H
Nakazawa
Mikio
M
Toyo-Oka
Teruhiko
T
D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D002154:Calpain / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000151:congenital / Q000503:physiopathology* / Q000628:therapy; D002463:Cell Membrane Permeability; D006224:Cricetinae; D000229:Dependovirus / Q000502:physiology; D004195:Disease Models, Animal; D016189:Dystrophin / Q000502:physiology*; D004789:Enzyme Activation; D015316:Genetic Therapy; D006333:Heart Failure / Q000139:chemically induced; D007545:Isoproterenol; D008647:Mesocricetus; D008954:Models, Biological; D051381:Rats; D049031:Sarcoglycans / Q000172:deficiency / Q000235:genetics; D012508:Sarcolemma / Q000502:physiology
D002135:Calcium-Binding Proteins; D016189:Dystrophin; D049031:Sarcoglycans; C033668:calpastatin; D002154:Calpain; D007545:Isoproterenol