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

Tomie Kawada, Fujiko Masui, Asaki Tezuka, Takashi Ebisawa, Hiroyuki Kumagai, Mikio Nakazawa, Teruhiko Toyo-Oka

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)73-81
Number of pages9
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1751
Issue number1
DOIs
Publication statusPublished - 2005 Aug 1

Keywords

  • Calpain
  • Dystrophin
  • Gene therapy
  • Heart failure
  • Proteolysis
  • δ-Sarcoglycan (SG)

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

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