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1 Department of Medicine, Geisinger Medical Center, Danville, PA, USA; Weis Center for Research, Geisinger Medical Center, Danville, PA, USA
2 Weis Center for Research, Geisinger Medical Center, Danville, PA, USA
3 Department of Internal Medicine (Cardiovascular Division), University of Virginia Health Sciences Center, Charlottesville, VA, USA
4 Weis Center for Research, Geisinger Medical Center, Danville, PA, USA; Department of Medicine, Geisinger Medical Center, Danville, PA, USA
* To whom correspondence should be addressed. E-mail: jcheung{at}geisinger.edu.
Phospholemman (PLM) expression was increased in rat hearts after myocardial infarction (MI). Overexpression of PLM in normal adult rat cardiac myocytes altered contractile function and cytosolic Ca2+ concentration ([Ca2+]i) homeostasis in a manner similar to that observed in post-MI myocytes. In this study, we tested whether PLM downregulation in normal adult rat myocytes resulted in contractility and [Ca2+]i transient changes opposite to those observed in post-MI myocytes. Compared with control myocytes infected with adenovirus (Adv) expressing green fluorescent protein (GFP) alone, myocytes infected with Adv expressing both GFP and antisense to rat PLM (rASPLM) had 23% less PLM protein (p<0.012) at 3 days, but no differences were found in sarcoplasmic reticulum (SR) Ca2+-ATPase, Na+/Ca2+ exchanger (NCX1), Na+-K+-ATPase and calsequestrin levels. SR Ca2+ uptake and whole cell capacitance were not affected by rASPLM treatment. Relaxation from caffeine-induced contracture was faster, and NCX1 current amplitudes were higher in rASPLM myocytes, indicating PLM downregulation enhanced NCX1 activity. In native rat cardiac myocytes, coimmunoprecipitation experiments indicated association of PLM with NCX1. At 0.6 mM [Ca2+]o, rASPLM myocytes had significantly (p<0.003) lower contraction and [Ca2+]i transient amplitudes than control GFP myocytes. At 5 mM [Ca2+]o, both contraction and [Ca2+]i transient amplitudes were higher in rASPLM myocytes. This pattern of contractile and [Ca2+]i transient behavior in rASPLM myocytes was opposite to that observed in post-MI rat myocytes. We conclude that downregulation of PLM in normal rat cardiac myocytes enhanced NCX1 function, and affected [Ca2+]i transient and contraction amplitudes. We suggest that PLM downregulation offers a potential therapeutic strategy for ameliorating contractile abnormalities in MI myocytes.
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