OneofresponsestoincreasedbloodpressureiscardiachypertrophythroughincreasedsizeofventricularmyocardialcellsleADIngtoincreasedthicknessoftheventricularwalls.Cardiachypertrophyallowsthehearttohandletheincreasedstresscausedbyelevatedbloodpressurebutisalsoariskfactorassociatedwithheartdisease.Cardiachypertrophyresultsfromcross-talkbetweenG-proteincoupledreceptorsignalingandtheEGFreceptorpathway.SeveralGPCRligandsareknowntostimulatecardiachypertrophy,includingfactorsthatregulatebloodpressuresuchasangiotensinIIandendothelin-1.ThesefactorsstimulatephospholipaseCthroughGqactivation,andtheproductionof1P3anddiacylglycerolsecondmessengers.PKC-deltaisactivatedbyDAGandinteractswiththemetalloproteinaseADAM12.ADAM12cleavesthemembrane-boundHB-EGFtoreleasesolubleEGFligandthatactivatesEGFreceptorinmyocardialcells.EGFreceptoractivationdownstreamthroughsmallGproteinsandtheMAPkinasepathwayultimatelyleadstocardiachypertrophy.SignalsbyGPCRligandssuchasangiotensinIIresultintranscriptionaltranslationofimmediateearlygeneslikefosandothergenesinvolvedinlong-termremodelingofhearttissueandthephysiologicalresponsetostressintheheartsuchastheatrialnatriureticfactor.FactorssuchastheAKTkinase,reactiveoxygenspecies(ROS)andNE-kBalsoareinvolvedinsignalingthatleadstohypertrophy,althoughtheirroleisnotyetclear.Blockingthispathwayatvariousstepsmaypreventheartdiseasethroughthepreventionofcardiachypertrophy,butmayalsohaveotherconsequences.

Contributor:GlennCroston,PhD.

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