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(Circulation Research. 2005;96:815.)
© 2005 American Heart Association, Inc.

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Adenoviral Gene Transfer of Mutant Phospholamban Rescues Contractile Dysfunction in Failing Rabbit Myocytes With Relatively Preserved SERCA Function

Mark T. Ziolo, Jody L. Martin, Julie Bossuyt, Donald M. Bers, Steven M. Pogwizd

From the Department of Physiology (M.T.Z., J.L.M., J.B., D.M.B.), Loyola University Chicago, Maywood, Ill; and the Department of Medicine (S.M.P.), University of Illinois at Chicago, Chicago, Ill.

Correspondence to Mark T. Ziolo, Department of Physiology and Cell Biology, Ohio State University, 304 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210-1218. E-mail ziolo.1{at}osu.edu

In heart failure (HF) a main factor in reduced contractility is reduced SR Ca²⁺ content and reversed force-frequency response (FFR), ie, from positive to negative. Our arrhythmogenic rabbit HF model exhibits decreased contractility mainly due to an increase in Na/Ca exchange (NCX) activity (with only modest decrease in SR Ca²⁺-ATPase (SERCA) function), similar to many end-stage HF patients. Here we test whether phospholamban (PLB) inhibition using a dominant-negative mutant PLB adenovirus (K3E/R14E, AdPLB-dn, with ß-galactosidase adenovirus as control) could enhance SERCA function and restore Ca²⁺ transients and positive FFR in ventricular myocytes from these HF rabbits. HF myocytes infected with AdPLB-dn (versus control) had enhanced Ca²⁺ transient amplitude (2.0±0.1 versus 1.6±0.05 F/F_o at 0.5 Hz, P<0.05) and had a positive FFR, whereas acutely isolated HF myocytes or those infected with Adßgal had negative FFR. Ca²⁺ transients declined faster in AdPLB-dn versus Adßgal myocytes (RT_50%: 317±29 versus 551±90 ms at 0.5 Hz, P<0.05) and had an increased SR Ca²⁺ load (3.5±0.3 versus 2.6±0.2 F/F_o at 0.5 Hz, P<0.05), indicative of increased SERCA function. Furthermore, this restoration of function was not due to changes in NCX or SERCA expression. Thus, increasing SERCA activity in failing myocytes by AdPLB-dn gene transfer reversed the contractile dysfunction (and restored positive FFR) by increasing SR Ca²⁺ load. This approach could enhance contractile function in failing hearts of various etiologies, even here where reduced SERCA activity is not the main dysfunction.

Key Words: heart failure • gene transfer • SERCA • phospholamban

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