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Excision of titin's cardiac PEVK spring element abolishes PKCalpha-induced increases in myocardial stiffness

Item Type:Article
Title:Excision of titin's cardiac PEVK spring element abolishes PKCalpha-induced increases in myocardial stiffness
Creators Name:Hudson, B.D. and Hidalgo, C.G. and Gotthardt, M. and Granzier, H.L.
Abstract:Protein Kinase C-alpha (PKCalpha) was recently reported to increase myocardial stiffness, an effect that was proposed to be due to phosphorylation of two highly conserved sites (S11878 and S12022) within the proline-gluatamic acid-valine-lysine (PEVK) rich spring element of titin. To test this proposal we investigated the effect of PKCalpha on phosphorylation and passive stiffness in a mouse model lacking the titin exons that contain these two phosphorylation sites, the PEVK knockout (KO). We used skinned, gelsolin-extracted, left ventricular, myocardium from wildtype and PEVK KO mice. Consistent with previous work we found that PKCalpha increased passive stiffness in the WT myocardium by 27 +/-6%. Importantly, this effect was completely abolished in KO myocardium. In addition, increases in the elastic and viscous moduli at a wide range of frequencies (properties important in diastolic filling) following PKCalpha incubation (27 +/-3% and 20 +/-4%, respectively) were also ablated in the KO. Back phosphorylation assays showed that titin phosphorylation following incubation with PKCalpha was significantly reduced by 36+/-12% in skinned PEVK KO myocardial tissues. The remaining phosphorylation in the KO suggests that PKCalpha sites exist in the titin molecule outside the PEVK region; these sites are not involved in increasing passive stiffness. Our results firmly support that the PEVK region of cardiac titin is phosphorylated by PKCalpha and that this increases passive tension. Thus, the PEVK spring element is the critical site of PKCalpha's involvement in passive myocardial stiffness.
Keywords:Titin, Passive Stiffness, Diastole, PKC, Postranslational Modification, PEVK, Animals, Mice
Source:Journal of Molecular and Cellular Cardiology
Page Range:972-978
Date:May 2010
Official Publication:https://doi.org/10.1016/j.yjmcc.2009.12.006
PubMed:View item in PubMed

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