A novel scheme of dystrophin disruption for the progression of advanced heart failure

• Published in: Biochimica et biophysica acta Vol. 1751; no. 1; pp. 73 - 81
• Main Authors: Kawada, Tomie, Masui, Fujiko, Tezuka, Asaki, Ebisawa, Takashi, Kumagai, Hiroyuki, Nakazawa, Mikio, Toyo-oka, Teruhiko
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2005
• Subjects: Animals; Calcium-Binding Proteins - biosynthesis; Calpain; Calpain - metabolism; Cardiomyopathy, Dilated - congenital; Cardiomyopathy, Dilated - physiopathology; Cardiomyopathy, Dilated - therapy; Cell Membrane Permeability; Cricetinae; Dependovirus - physiology; Disease Models, Animal; Dystrophin; Dystrophin - physiology; Enzyme Activation; Gene therapy; Genetic Therapy; Heart failure; Heart Failure - chemically induced; Isoproterenol; Mesocricetus; Models, Biological; Proteolysis; Rats; Sarcoglycans - deficiency; Sarcoglycans - genetics; Sarcolemma - physiology; δ-Sarcoglycan (SG); Heart failure; δ-SG; LVP; Calpain; CM; DCM; rAAV; DAP; HCM; Proteolysis; δ-Sarcoglycan (SG); Gene therapy; Dystrophin
• ISSN: 1570-9639; 0006-3002; 1878-1454
• DOI: 10.1016/j.bbapap.2005.01.001

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 δ-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 δ-SG gene in vivo, these pathological alterations and the animals' survival improved. Furthermore, dystrophin but not δ-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.