Activation of the Ca++/calmodulin-dependent protein kinase has also been implicated in the activation of the transcription factor myocyte enhancer factor 2 (MEF2) by promoting the dissociation (nuclear export) of an inhibitor of MEF2, namely histone deacetylase (HDAC). The impaired β-adrenergic response of cardiac muscle after chronic pressure overload involves, at least in part, a decrease in β-adrenergic receptors due to internalization. Both phosphatidylinositol-3-kinase (PI3K) and β-adrenergic receptor kinase 1 have been implicated in the internalization of β-adrenergic receptors. Heart failure, a leading cause of death, can be seen with thickening of the walls of the ventricle or with dilation (i.e., increased volume) of the ventricles. Results of studies suggest that dilated cardiomyopathy can be prevented in an animal model by downregulating phospholamban, which typically inhibits SERCA. The mechanism underlying this preventive effect of phospholamban downregulation is thought to involve an increase in Ca++ uptake activity in the SR. Increased activity of SERCA would facilitate relaxation of the heart as a result of rapid Ca++ uptake by the SR. In addition, the force of contraction is increased because more Ca++ is available for release. Increased Ca++ uptake by the SR may also decrease activation of the Ca++-dependent phosphatases that have been implicated in the development of cardiac hypertrophy. There is evidence that cardiac hypertrophy may not be associated with some functional impairments. Intermittent aortic constrictions, for example, result in decreased β-adrenergic signaling, decreased capillary density, and decreased SERCA2 levels, without evidence of hypertrophy. Activation of PI3K appears to be involved in this response. Calcium-dependent activation of calcineurin and calmodulin-dependent protein kinase have been implicated in the development of cardiac hypertrophy and involve activation of the following transcription factors: nuclear factor of activated T cells (NFAT), transcription factor binding to DNA sequence GATA (GATA), and myocyte enhancer factor 2 (MEF2). Cabin, calcineurin-binding protein/inhibitor; CaMK, Ca++/calmodulin-dependent protein kinase; CsA, cyclosporine; GSK3, glycogen synthase kinase 3; HDAC, histone deacetylase; MCIP, modulatory calcineurin-interacting protein. (Redrawn from Olson EN, Williams RS. Calcineurin signaling and muscle remodeling. Cell. 2000;101:689-692.)
Amodestelevationinintracellular[Ca++](asaresultofincreasedcontractileactivity,forexample),hasbeenproposedtoactivateaCa++/calmodulin-dependentproteinphosphatase(calcineurin) thatcandephosphorylatethetranscriptionfactornuclear factor of activated T cells (NFAT), therebyfacilitatingtranslocationofNFATtothenucleusandultimatelypromotingproteinsynthesisandthushypertrophy(
Fig.13.7 ).ActivationofCa++/calmodulin-dependentproteinkinasehasalsobeenimplicatedinactivationofthetranscriptionfactormyocyte enhancer factor 2 (MEF2) bypromotingthedissociation(nuclearexport)ofaninhibitorofMEF2(namely,histone deacetylase [HDAC]).
Theimpairedβ-adrenergicresponseofcardiacmuscleafterchronicpressureoverloadinvolves,atleastinpart,adecreaseinβ-adrenergicreceptorsbecauseofinternalization.Bothphosphatidylinositol-3-kinase (PI3K) andβ-adrenergic receptor kinase 1 havebeenimplicatedintheinternalizationofβ-adrenergicreceptors.
Highbloodpressure,defectsinheartvalves,andventricularwallsweakenedasaresultofmyocardialinfarctioncanallleadtoheartfailure,aleadingcauseofdeath.Heartfailuremaybeseenwiththickeningofthewallsoftheventricleorwithdilation(i.e.,increasedvolume)oftheventricles.
Resultsofstudiessuggestthatdilatedcardiomyopathycanbepreventedinananimalmodelbydownregulatingphospholamban.ThemechanismunderlyingthispreventiveeffectofphospholambandownregulationisthoughttoinvolveanincreaseinCa++ uptakeactivityintheSRbecausephospholambantypicallyinhibitsSERCA.IncreasedactivityofSERCAwouldfacilitaterelaxationoftheheartasaresultofrapidCa++ uptakebytheSR.Inaddition,theforceofcontractionisincreasedbecausemoreCa++ isavailableforrelease.IncreasedCa++ uptakebytheSRmayalsodecreaseactivationoftheCa++-dependentphosphatasesthathavebeenimplicatedinthedevelopmentofcardiachypertrophy.
There is evidence that cardiac hypertrophy may not be associated with some functional impairments. Intermittent aortic constrictions, for example, result in decreased β-adrenergic signaling, decreased capillary density, and decreased SERCA2 levels, without evidence of hypertrophy. Activation of PI3K appears to be involved in this response.
278 SECTION3Berne & Levy Physiology Activity Ca++ Other transducers? Other effectors? Reprogramming Gene Expression Myocyte Hypertrophy/Tissue Remodeling CalcineurinCaMK Other targets? NFAT NFAT GSK3 HDAC CsA Cabin MCIP Agonists MEF2 GATA P •Fig. 13.7 Calcium-dependentactivationofcalcineurinandcalmodulin-dependentproteinkinasehavebeenimplicatedinthedevelopmentofcardiachypertrophyandinvolveactivationofthefollowingtranscriptionfactors:nuclearfactorofactivatedTcells(NFAT),transcriptionfactorbindingtoDNAsequenceGATA(GATA),andmyocyteenhancerfactor2(MEF2).Cabin,calcineurin-bindingprotein/inhibitor;CaMK,Ca++/calmodulin-dependentproteinkinase;CsA,cyclosporine;GSK3,glycogensynthasekinase3;HDAC,histonedeacetylase;MCIP,modulatorycalcineurin-interactingprotein.(RedrawnfromOlsonEN,WilliamsRS.Calcineurinsignalingandmuscleremodeling.Cell. 2000;101:689-692.) 1.