title: Pleiotropic Effects of Simvastatin on Some Calcium Regulatory and Myofibrillar Proteins in Ischemic/Reperfused Heart: Causality of Statins Cardioprotection?
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.forename: Adrian
authors.initials: A
authors.lastname: Szobi
authors.forename: Martin
authors.initials: M
authors.lastname: Lichy
authors.forename: Slavka
authors.initials: S
authors.lastname: Carnicka
authors.forename: Dezider
authors.initials: D
authors.lastname: Pancza
authors.forename: Pavel
authors.initials: P
authors.lastname: Svec
authors.forename: Tana
authors.initials: T
authors.lastname: Ravingerova
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Odbojarov 10, 832 32, Slovakia.
authors.forename: Adriana
authors.initials: A
authors.lastname: Adameova
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008055:Lipids / Q000097:blood; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D009124:Muscle Proteins; D019821:Simvastatin; D002118:Calcium
keywords: CaMKII; Ischemia-reperfusion; cMyBP-C; heart; protein phosphatase; simvastatin