Abstract
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 contractile dysfunction.
Objective: With this background, we tested a hypothesis that simvastatin influences signaling of Ca2+/calmodulindependent 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 of Thr287. Activation of its downstreams, such as phospholamban (PLN) and cardiac myosin-binding protein C (cMyBP-C) at Thr17 and Ser282, respectively, was in accordance with the levels of pThr287-CaMKIIδ. 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.Keywords: Ischemia-reperfusion, heart, simvastatin, CaMKII, protein phosphatase, cMyBP-C.
Current Pharmaceutical Design
Title:Pleiotropic Effects of Simvastatin on Some Calcium Regulatory and Myofibrillar Proteins in Ischemic/Reperfused Heart: Causality of Statins Cardioprotection?
Volume: 22 Issue: 42
Author(s): Adrian Szobi, Martin Lichy, Slavka Carnicka, Dezider Pancza, Pavel Svec, Tana Ravingerova and Adriana Adameova
Affiliation:
Keywords: Ischemia-reperfusion, heart, simvastatin, CaMKII, protein phosphatase, cMyBP-C.
Abstract: 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 contractile dysfunction.
Objective: With this background, we tested a hypothesis that simvastatin influences signaling of Ca2+/calmodulindependent 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 of Thr287. Activation of its downstreams, such as phospholamban (PLN) and cardiac myosin-binding protein C (cMyBP-C) at Thr17 and Ser282, respectively, was in accordance with the levels of pThr287-CaMKIIδ. 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.Export Options
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Cite this article as:
Szobi Adrian, Lichy Martin, Carnicka Slavka, Pancza Dezider, Svec Pavel, Ravingerova Tana and Adameova Adriana, Pleiotropic Effects of Simvastatin on Some Calcium Regulatory and Myofibrillar Proteins in Ischemic/Reperfused Heart: Causality of Statins Cardioprotection?, Current Pharmaceutical Design 2016; 22 (42) . https://dx.doi.org/10.2174/1381612822666160813235243
DOI https://dx.doi.org/10.2174/1381612822666160813235243 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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