The atypical 'b' splice variant of phospholipase Cβ1 promotes cardiac contractile dysfunction.
The activity of the early signaling enzyme, phospholipase Cβ1b (PLCβ1b), is selectively elevated in diseased myocardium and activity increases with disease progression. We aimed to establish the contribution of heightened PLCβ1b activity to cardiac pathology. PLCβ1b, the alternative splice variant, PLCβ1a, and a blank virus were expressed in mouse hearts using adeno-associated viral vectors (rAAV6-FLAG-PLCβ1b, rAAV6-FLAG-PLCβ1a, or rAAV6-blank) delivered intravenously (IV). Following viral delivery, FLAG-PLCβ1b was expressed in all of the chambers of the mouse heart and was localized to the sarcolemma. Heightened PLCβ1b expression caused a rapid loss of contractility, 4-6 weeks, that was fully reversed, within 5 days, by inhibition of protein kinase Cα (PKCα). PLCβ1a did not localize to the sarcolemma and did not affect contractile function. Expression of PLCβ1b, but not PLCβ1a, caused downstream dephosphorylation of phospholamban and depletion of the Ca(2+) stores of the sarcoplasmic reticulum. We conclude that heightened PLCβ1b activity observed in diseased myocardium contributes to pathology by PKCα-mediated contractile dysfunction. PLCβ1b is a cardiac-specific signaling system, and thus provides a potential therapeutic target for the development of well-tolerated inotropic agents for use in failing myocardium.
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004 Victoria, Australia.
David R
DR
Grubb
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004 Victoria, Australia.
Bryony
B
Crook
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004 Victoria, Australia.
Yi
Y
Ma
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004 Victoria, Australia.
Jieting
J
Luo
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004 Victoria, Australia.
Hong Wei
HW
Qian
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004 Victoria, Australia.
Xiao-Ming
XM
Gao
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004 Victoria, Australia.
Helen
H
Kiriazis
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004 Victoria, Australia.
Xiao-Jun
XJ
Du
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004 Victoria, Australia.
Paul
P
Gregorevic
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, 3004 Victoria, Australia. Electronic address: liz.woodcock@bakeridi.edu.au.
Elizabeth A
EA
Woodcock
D061605:Administration, Intravenous; D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000229:Dependovirus / Q000378:metabolism; D005355:Fibrosis; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D054799:Phospholipase C beta / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014463:Ultrasonography; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D054799:Phospholipase C beta; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D000099211:Phospholamban
AAV; Cardiac contractility; Gene therapy; Signaling pathways