Background: It is known that statins possess beneficial cardioprotective effects irrespective of lipidlowering
action and that cardiac injury due ischemia/reperfusion is associated with Ca2+ dysregulation resulting in
Objective: With this background, we tested a hypothesis that simvastatin influences signaling of Ca2+
protein kinase IIδ (CaMKIIδ), a protein kinase regulating both Ca2+
homeostasis and thick filament
function, and thereby might underlie the mitigation of ischemia/reperfusion (I/R)-induced cardiac dysfunction.
Method: Isolated hearts of control and simvastatin-treated (p.o. 10 mg/kg, 5 days) rats were subjected to global I
and R and Western blotting was used to study the expression/activation of certain signaling proteins.
Results: Simvastatin treatment did not modify the plasma lipid levels; however, it recovered depressed cardiac
performance and reduced reperfusion arrhythmias without affecting the activation of CaMKIIδ through phosphorylation
. Activation of its downstreams, such as phospholamban (PLN) and cardiac myosin-binding
protein C (cMyBP-C) at Thr17
, respectively, was in accordance with the levels of pThr287
Total expression of these proteins, however, did not follow the same pattern and was either unchanged (CaMKIIδ,
cMYBP-C) or increased (PLN). Likewise, PLN/SERCA2a (sarco/endoplasmic reticulum Ca2+
-ATPase 2a) ratio
in I/R hearts was unaffected by the treatment. On the other hand, simvastatin reversed the increased protein expression
of protein phosphatase 1β (PP1β), but not protein phosphatase 2A (PP2A), in I/R hearts.
Conclusion: A lower rate of dephosphorylation and thereby a delay in inactivation of phosphorylated proteins
due to a decrease in PP1β, rather than effects on phosphorylation of CaMKIIδ and its downstreams, such as PLN
and cMyBP-C, may underlie beneficial effects of simvastatin in I/R hearts.