Dilated cardiomyopathy in two transgenic mouse lines expressing activated G protein alpha(q): lack of correlation between phospholipase C activation and the phenotype.
We previously described a transgenic mouse line (alpha(q)*52) in which cardiac-specific expression of activated G alpha(q)protein (HA alpha(q)*) leads to activation of phospholipase C beta (PLC beta), the immediate downstream target of HA alpha(q)*, with subsequent development of cardiac hypertrophy and dilation. We now describe a second, independent line in the same genetic background (alpha(q)*44h) with lower expression of HA alpha(q)* protein that ultimately results in the same phenotype: dilated cardiomyopathy (DCM) with severely impaired left ventricular systolic function (assessed by M-mode and 2D echocardiography), but with a much delayed disease onset. We asked if PLC activation correlates with the development of the phenotype. At 12-14 months, 65% of alpha(q)*44h mice still had normal cardiac function and ventricular weight/body weight ratios (VW/BW). However, their basal PLC activity, which began to increase in ventricles at 6 months, was threefold higher than in wild-type by 12 months. This increase was even more pronounced than in 2.5-month-old alpha(q)*52 mice, in which a twofold increase was accompanied by a 25% increase in VW/BW. Furthermore, at 12-14 months the increase in PLC activity in alpha(q)*44h mice with and without DCM was comparable. Thus, the delayed time course in alpha(q)*44h mice unmasked a lack of correlation between PLC activation and development of DCM in response to HA alpha(q)* expression, suggesting a role for additional pathways and/or mechanisms. It also revealed a differential temporal regulation of protein kinase C isoform expression. The markedly different ages of disease onset in these two mouse lines provide a model for studying both genetic modifying factors and potential environmental influences in DCM.
Mende
U
U
Department of Medicine, Cardiovascular Divison, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Semsarian
C
C
Martins
D C
DC
Kagen
A
A
Duffy
C
C
Schoen
F J
FJ
Neer
E J
EJ
D000375:Aging; D000818:Animals; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006352:Heart Ventricles; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D015398:Signal Transduction; D013997:Time Factors; D010738:Type C Phospholipases / Q000096:biosynthesis*
D007527:Isoenzymes; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins