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Circulation Research. 2005
Published online before print March 24, 2005, doi: 10.1161/01.RES.0000163981.97262.3b
A more recent version of this article appeared on April 29, 2005
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Submitted on October 18, 2004
Revised on March 15, 2005
Accepted on March 16, 2005

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 ; and 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.

* To whom correspondence should be addressed. 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 {beta}-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/Fo at 0.5 Hz, P<0.05) and had a positive FFR, whereas acutely isolated HF myocytes or those infected with Ad{beta}gal had negative FFR. Ca2+ transients declined faster in AdPLB-dn versus Ad{beta}gal myocytes (RT50%: 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/Fo 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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