Cardiovascular Research

Cardiovascular Research 2002 53(2):382-391; doi:10.1016/S0008-6363(01)00489-8
© 2002 by European Society of Cardiology

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Copyright © 2001, European Society of Cardiology

Reduced level of serine¹⁶ phosphorylated phospholamban in the failing rat myocardium: a major contributor to reduced SERCA2 activity

Jørn B Sande^a,*, Ivar Sjaastad^a, Ingvild B Hoen^a, Janny Bøkenes^a, Theis Tønnessen^a,b, Even Holt^a,c, Per K Lunde^a and Geir Christensen^a

^aInstitute for Experimental Medical Research, Ullevaal University Hospital, Kirkeveien 166, N-0407 Oslo, Norway
^bDepartment of Cardiothoracic Surgery, Ullevaal University Hospital, N-0407 Oslo, Norway
^cCardiological Department, Baerum Hospital, N-1306 Baerum Postterminal, Norway

^* Corresponding author. Tel.: +47-2301-6795; fax: +47-2301-6799 j.b.sande{at}ioks.uio.no

Objective: Heart failure is associated with alterations in contractile parameters and accompanied by abnormalities in intracellular calcium homeostasis. Sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2) and phospholamban (PLB) are important in intracellular calcium cycling. The aim of the present study was to examine mechanisms causing reductions in SERCA2 activity in the failing heart. Methods: Myocardial infarction (MI) was induced in male Wistar rats, and animals with congestive heart failure were examined 6 weeks after the primary operation. Results: Serine¹⁶ monomeric and pentameric phosphorylated PLB were significantly downregulated (50 and 55%, respectively), whereas threonine¹⁷ phosphorylated PLB was unchanged in failing compared to sham hearts. Protein phosphatases 1 and 2A were significantly upregulated (26 and 42%, respectively) and phosphatase 2C significantly downregulated (29%), whereas the level of protein kinase A regulatory subunit II remained unchanged during heart failure. Increasing PLB phosphorylation by forskolin in isolated cardiomyocytes after inhibition of the Na⁺–Ca²⁺ exchanger activity had significantly greater effect on SERCA2 activity in failing than in sham cells (49 and 20% faster transient decline, respectively). Decreasing PLB phosphorylation by the protein kinase A inhibitor H89 had significantly less effect on SERCA2 activity in failing compared to sham cardiomyocytes (20 and 75% slower transient decline, respectively). Conclusion: The observed changes in SERCA2 activity after increasing and decreasing serine¹⁶ PLB phosphorylation in cardiomyocytes from sham and failing hearts, suggest that the observed reduction in serine¹⁶ PLB phosphorylation is one major factor determining the reduced SERCA2 activity in heart failure after MI.

KEYWORDS Calcium (cellular); Contractile function; Heart failure; Infarction; Myocytes; SR (function)

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