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@article{Sheehan:2018:10.3389/fphys.2018.00243,
author = {Sheehan, A and Messer, A and Papadaki, M and Choudhry, A and Kren, V and Biedermann, D and Blagg, B and Khandelwahl, A and Marston, SB},
doi = {10.3389/fphys.2018.00243},
journal = {Frontiers in Physiology},
title = {Molecular defects in cardiac myofilament Ca2+- regulation due to cardiomyopathy-linked mutations can be reversed by small molecules binding to troponin},
url = {http://dx.doi.org/10.3389/fphys.2018.00243},
volume = {9},
year = {2018}
}

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TY  - JOUR
AB  - The inherited cardiomyopathies, hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are relatively common, potentially life-threatening and currently untreatable. Mutations are often in the contractile proteins of cardiac muscle and cause abnormal Ca2+regulation viatroponin.  HCM is usually linked to higher myofilament Ca2+-sensitivitywhilst in both HCM and DCM mutant tissue there is oftenan uncoupling of the relationship between troponin I (TnI) phosphorylation by PKA and modulation of myofilament Ca2+-sensitivity, essential for normal responses to adrenaline. The adrenergic response is blunted, and this may predispose the heartto failure under stress. Atpresenttherearenocompoundsorinterventionsthatcanpreventortreatsarcomericcardiomyopathies.Thereisaneedfornoveltherapiesthatactatamorefundamentalleveltoaffectthediseaseprocess.Wedemonstratedthatepigallocatechin-3gallate(EGCG)wasfoundtobecapableofrestoringthecoupledrelationshipbetweenCa2+-sensitivityandTnIphosphorylationinmutantthinfilamentstonormalinvitro,independentofthemutation(15mutationstested).Wehavelabelledthisproperty“re-coupling”.TheactionofEGCGinvitrotoreversetheabnormalitycausedbymyopathicmutationswouldappeartobeanidealpharmaceuticalprofilefortreatmentofinheritedHCMandDCMbutEGCGisknowntobepromiscuousinvivoandisthusunsuitableastherapeuticdrug.Wethereforeinvestigatedwhetherotherstructurallyrelatedcompoundscanre-couplemyofilamentswithouttheseoff-targeteffects.We used the quantitative in vitromotility assay to screen 40 compounds,related to C-terminal Hsp90 inhibitors, and found 23 that can re-couple mutant myofilaments.  There is no correlation between re-couplers and Hsp90 inhibitors. The Ca2+-sensitivity shift due to TnIphosphorylation was restored to 2.2±0.01 –fold (n=19) compared to 2.0±.24 fold (n=7) in wild-type thin filaments. Many of these compounds were either pure re-couplers or pure desensitisers,indicating these properties are independent; moreover,re-
AU  - Sheehan,A
AU  - Messer,A
AU  - Papadaki,M
AU  - Choudhry,A
AU  - Kren,V
AU  - Biedermann,D
AU  - Blagg,B
AU  - Khandelwahl,A
AU  - Marston,SB
DO  - 10.3389/fphys.2018.00243
PY  - 2018///
SN  - 1664-042X
TI  - Molecular defects in cardiac myofilament Ca2+- regulation due to cardiomyopathy-linked mutations can be reversed by small molecules binding to troponin
T2  - Frontiers in Physiology
UR  - http://dx.doi.org/10.3389/fphys.2018.00243
UR  - http://hdl.handle.net/10044/1/57853
VL  - 9
ER  -

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