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Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats
Yoshitaka Iwanaga, … , Kenneth R. Chien, John Ross Jr.
Yoshitaka Iwanaga, … , Kenneth R. Chien, John Ross Jr.
Published March 1, 2004
Citation Information: J Clin Invest. 2004;113(5):727-736. https://doi.org/10.1172/JCI18716.
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Article Cardiology Article has an altmetric score of 3

Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats

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Abstract

Ablation or inhibition of phospholamban (PLN) has favorable effects in several genetic murine dilated cardiomyopathies, and we showed previously that a pseudophosphorylated form of PLN mutant (S16EPLN) successfully prevented progressive heart failure in cardiomyopathic hamsters. In this study, the effects of PLN inhibition were examined in rats with heart failure after myocardial infarction (MI), a model of acquired disease. S16EPLN was delivered into failing hearts 5 weeks after MI by transcoronary gene transfer using a recombinant adeno-associated virus (rAAV) vector. In treated (MI-S16EPLN, n = 16) and control (MI-saline, n = 18) groups, infarct sizes were closely matched and the left ventricle was similarly depressed and dilated before gene transfer. At 2 and 6 months after gene transfer, MI-S16EPLN rats showed an increase in left ventricular (LV) ejection fraction and a much smaller rise in LV end-diastolic volume, compared with progressive deterioration of LV size and function in MI-saline rats. Hemodynamic measurements at 6 months showed lower LV end-diastolic pressures, with enhanced LV function (contractility and relaxation), lowered LV mass and myocyte size, and less fibrosis in MI-S16EPLN rats. Thus, PLN inhibition by in vivo rAAV gene transfer is an effective strategy for the chronic treatment of an acquired form of established heart failure.

Authors

Yoshitaka Iwanaga, Masahiko Hoshijima, Yusu Gu, Mitsuo Iwatate, Thomas Dieterle, Yasuhiro Ikeda, Moto-o Date, Jacqueline Chrast, Masunori Matsuzaki, Kirk L. Peterson, Kenneth R. Chien, John Ross Jr.

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Figure 1

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Enhanced shortening and SR calcium cycling in isolated adult rat cardiom...
Enhanced shortening and SR calcium cycling in isolated adult rat cardiomyocytes treated with S16EPLN. Ventricular cardiomyocytes were isolated from adult Wistar rats according to the protocol described by Zho et al. (30). Cells were transfected with adenovirus vectors expressing LacZ (Adeno-LacZ) or S16EPLN (Adeno-S16EPLN) at a multiplicity of infection of 100 and cultured for 36 hours. Nearly 100% efficiency of transfection was confirmed by β-gal staining of Adeno-LacZ–treated cells. Thereafter, both Adeno-LacZ–treated cells and Adeno-S16EPLN–treated cells were loaded with fura-2/AM, and cell shortening and changes in intracellular-calcium concentration were monitored. (A and B) Representative tracings of cell length and fura-2 340/380 ratio, an index of calcium concentration. (C–E) Indices of cell shortening (percentage fractional shortening [% FS] and –dL/dt) and relaxation (+dL/dt). (F and G) The averaged peak amplitude of an index of calcium transient (F) and the averaged decay time constant of the descending limb of calcium transient (G). Data represent mean ± SE and are accumulated from five independent experiments from five animals. A total of 40 cells were measured for each treatment group. *P < 0.05 between groups. L, length.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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