Effects of phospholemman downregulation on contractility and [Ca2+]itransients in adult rat cardiac myocytes

Authors:
  • XZXue-Qian Zhang
    Xue-Qian Zhang
  • BABelinda A. Ahlers
    Belinda A. Ahlers
  • AQAnwer Qureshi
    Anwer Qureshi
  • LCLois L. Carl
    Lois L. Carl
  • JSJianliang Song
    Jianliang Song
  • ATAmy L. Tucker
    Amy L. Tucker
  • JMJ. Paul Mounsey
    J. Paul Mounsey
  • JMJ. Randall Moorman
    J. Randall Moorman
  • LRLawrence I. Rothblum
    Lawrence I. Rothblum
  • TZThomas S. Zhang
    Thomas S. Zhang
  • JCJoseph Y. Cheung
    Joseph Y. Cheung
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Abstract
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+]itransient 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 rat antisense 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 that PLM downregulation enhanced NCX1 activity. In native rat cardiac myocytes, coimmunoprecipitation experiments indicated an association of PLM with NCX1. At 0.6 mM [Ca2+]o, rASPLM myocytes had significantly ( P < 0.003) lower contraction and [Ca2+]itransient amplitudes than control GFP myocytes. At 5 mM [Ca2+]o, both contraction and [Ca2+]itransient amplitudes were higher in rASPLM myocytes. This pattern of contractile and [Ca2+]itransient 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+]itransient and contraction amplitudes. We suggest that PLM downregulation offers a potential therapeutic strategy for ameliorating contractile abnormalities in MI myocytes.

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