Selective activation of the "b" splice variant of phospholipase Cbeta1 in chronically dilated human and mouse atria.
Atrial fibrillation (AF) is commonly associated with chronic dilatation of the left atrium, both in human disease and animal models. The immediate signaling enzyme phospholipase C (PLC) is activated by mechanical stretch to generate the Ca2+-releasing messenger inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) and sn-1,2-diacylglycerol (DAG), an activator of protein kinase C subtypes. There is also evidence that heightened activity of PLC, caused by the receptor coupling protein Gq, can contribute to atrial remodelling. We examined PLC activation in right and left atrial appendage from patients with mitral valve disease (VHD) and in a mouse model of dilated cardiomyopathy caused by transgenic overexpression of the stress-activated protein kinase, mammalian sterile 20 like kinase 1 (Mst1) (Mst1-TG). PLC activation was heightened 6- to 10-fold in atria from VHD patients compared with right atrial tissue from patients undergoing coronary artery bypass surgery (CABG) and was also heightened in the dilated atria from Mst1-TG. PLC activation in human left atrial appendage and in mouse left atria correlated with left atrial size, implying a relationship between PLC activation and chronic dilatation. Dilated atria from human and mouse showed heightened expression of PLCbeta1b, but not of other PLC subtypes. PLCbeta1b, but not PLCbeta1a, caused apoptosis when overexpressed in neonatal rat cardiomyocytes, suggesting that PLCbeta1b may contribute to chamber dilatation. The activation of PLCbeta1b is a possible therapeutic target to limit atrial remodelling in VHD patients.
Woodcock
Elizabeth A
EA
Molecular Cardiology Laboratory, Baker IDI, Heart and Diabetes Institute, PO Box 6492, St. Kilda Road Central, Melbourne, 8008, Victoria, Australia. liz.woodcock@bakerIDI.edu.au
Grubb
David R
DR
Filtz
Theresa M
TM
Marasco
Silvana
S
Luo
Jieting
J
McLeod-Dryden
Tiffany J
TJ
Kaye
David M
DM
Sadoshima
Junichi
J
Du
Xiao-Jun
XJ
Wong
Chiew
C
McMullen
Julie R
JR
Dart
Anthony M
AM
D000818:Animals; D000831:Animals, Newborn; D020517:Atrial Appendage / Q000378:metabolism / Q000473:pathology; D001281:Atrial Fibrillation / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006325:Heart Atria; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008944:Mitral Valve Insufficiency / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D054799:Phospholipase C beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D054799:Phospholipase C beta