title: A novel paradigm for therapeutic basis of advanced heart failure--assessment by gene therapy.
abstract: The precise mechanism(s) of the progression of advanced heart failure (HF) should be determined to establish strategies for its treatment or prevention. Based on pathological, molecular, and physiological findings in 3 animal models and human cases, we propose a novel scheme that a vicious cycle formed by increased sarcolemma (SL) permeability, preferential activation of calpain over calpastatin, and translocation and cleavage of dystrophin (Dys) commonly lead to advanced HF. The aim of this article was to assess our recent paradigm that disruption of myocardial Dys is a final common pathway to advanced HF, irrespective of its hereditary or acquired origin, but not intended to provide a comprehensive overview of the various factors that may be involved in the course of HF in different clinical settings. In addition, each component of Dys-associated proteins (DAP) was heterogeneously degraded in vivo and in vitro, i.e. Dys and alpha-sarcoglycan (SG) were markedly destroyed using isolated calpain 2, while delta-SG was not degraded at all. The up-regulation of calpain 2 was confirmed through previously published data that remain insufficient for precise evaluation, supporting our new scheme that the activation of calpain(s) is involved in the steady process of Dys cleavage. In addition, somatic gene therapy is discussed as a potential option to ameliorate the physiological/metabolic indices and to improve the prognosis.
authors.affiliation: Division of Pharmacy, Niigata University of Medical and Dental Hospital, Niigata 951-8520, Japan.
authors.forename: Tomie
authors.initials: T
authors.lastname: Kawada
authors.forename: Fujiko
authors.initials: F
authors.lastname: Masui
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kumagai
authors.forename: Miki
authors.initials: M
authors.lastname: Koshimizu
authors.forename: Mikio
authors.initials: M
authors.lastname: Nakazawa
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Toyo-Oka
mesh_terms: D000818:Animals; D002154:Calpain / Q000009:adverse effects / Q000378:metabolism / Q000502:physiology*; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D016189:Dystrophin / Q000378:metabolism / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000209:etiology / Q000235:genetics / Q000628:therapy; D006801:Humans; D009203:Myocardial Infarction / Q000150:complications; D049031:Sarcoglycans / Q000145:classification / Q000378:metabolism / Q000502:physiology*; D014161:Transduction, Genetic / Q000379:methods
chemical_list: D016189:Dystrophin; D049031:Sarcoglycans; D002154:Calpain