Translocation and cleavage of myocardial dystrophin as a common pathway to advanced heart failure: a scheme for the progression of cardiac dysfunction.
Advanced heart failure (HF) is the leading cause of death in developed countries. The mechanism underlying the progression of cardiac dysfunction needs to be clarified to establish approaches to prevention or treatment. Here, using TO-2 hamsters with hereditary dilated cardiomyopathy, we show age-dependent cleavage and translocation of myocardial dystrophin (Dys) from the sarcolemma (SL) to the myoplasm, increased SL permeability in situ, and a close relationship between the loss of Dys and hemodynamic indices. In addition, we observed a surprising correlation between the amount of Dys and the survival rate. Dys disruption is not an epiphenomenon but directly precedes progression to advanced HF, because long-lasting transfer of the missing delta-SG gene to degrading cardiomyocytes in vivo with biologically nontoxic recombinant adenoassociated virus (rAAV) vector ameliorated all of the pathological features and changed the disease prognosis. Furthermore, acute HF after isoproterenol toxicity and chronic HF after coronary ligation in rats both time-dependently cause Dys disruption in the degrading myocardium. Dys cleavage was also detected in human hearts from patients with dilated cardiomyopathy of unidentified etiology, supporting a scheme consisting of SL instability, Dys cleavage, and translocation of Dys from the SL to the myoplasm, irrespective of an acute or chronic disease course and a hereditary or acquired origin. Hereditary HF may be curable with gene therapy, once the responsible gene is identified and precisely corrected.
Toyo-Oka
Teruhiko
T
Department of Pathophysiology and Internal Medicine, University of Tokyo, Tokyo 113-0033, Japan. toyooka.31m@hotmail.com
Kawada
Tomie
T
Nakata
Jumi
J
Xie
Han
H
Urabe
Masashi
M
Masui
Fujiko
F
Ebisawa
Takashi
T
Tezuka
Asaki
A
Iwasawa
Kuniaki
K
Nakajima
Toshiaki
T
Uehara
Yoshio
Y
Kumagai
Hiroyuki
H
Kostin
Sawa
S
Schaper
Jutta
J
Nakazawa
Mikio
M
Ozawa
Keiya
K
D000818:Animals; D016189:Dystrophin / Q000378:metabolism*; D006439:Hemodynamics; D006801:Humans; D006868:Hydrolysis; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats
D016189:Dystrophin