title: Expressing an inhibitor of PLCβ1b sustains contractile function following pressure overload.
abstract: The activity of phospholipase Cβ1b (PLCβ1b) is selectively elevated in failing myocardium and cardiac expression of PLCβ1b causes contractile dysfunction. PLCβ1b can be selectively inhibited by expressing a peptide inhibitor that prevents sarcolemmal localization. The inhibitory peptide, PLCβ1b-CT was expressed in heart from a mini-gene using adeno-associated virus (rAAV6-PLCβ1b-CT). rAAV6-PLCβ1b-CT, or blank virus, was delivered IV (4×10(9)vg/g body weight) and trans-aortic-constriction (TAC) or sham-operation was performed 8weeks later. Expression of PLCβ1b-CT prevented the loss of contractile function, eliminated lung congestion and improved survival following TAC with either a 'moderate' or 'severe' pressure gradient. Hypertrophy was attenuated but not eliminated. Expression of the PLCβ1b-CT peptide 2-3weeks after TAC reduced contractile dysfunction and lung congestion, without limiting hypertrophy. PLCβ1b inhibition ameliorates pathological responses following acute pressure overload. The targeting of PLCβ1b to the sarcolemma provides the basis for the development of a new class of inotropic agent.
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne 3004, Victoria, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Grubb
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne 3004, Victoria, Australia.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne 3004, Victoria, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Kiriazis
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne 3004, Victoria, Australia.
authors.forename: Aya
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne 3004, Victoria, Australia.
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne 3004, Victoria, Australia.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Du
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne 3004, Victoria, Australia. Electronic address: liz.woodcock@bakeridi.edu.au.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Woodcock
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D006332:Cardiomegaly / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004452:Echocardiography; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006439:Hemodynamics; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics*; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics* / Q000494:pharmacology; D054799:Phospholipase C beta / Q000737:chemistry / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014161:Transduction, Genetic
chemical_list: D010446:Peptide Fragments; D012333:RNA, Messenger; D054799:Phospholipase C beta; C518034:Plcb1 protein, mouse
keywords: Cardiac hypertrophy; Heart failure; Inotropic agent; Mouse