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 car diac-specific expression of activated Gag protein (HA alpha (q)*) leads to activation of phospholipase C beta (PLC beta), the immediate downstream tar get of HA alpha (q)*. with subsequent development: of cardiac hypertrophy a nd 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-m ode and 2D echocardiography), but with a much delayed disease onset. We ask ed if PLC activation correlates with the development of the phenotype. At 1 2-14 months, 65% of alpha (q)*44h mice still had normal cardiac function an d ventricular weight/body weight ratios (VW/BW). However, their basal PLC a ctivity, which began to increase in ventricles at 6 months, was threefold h igher than in wild-type by 12 months. This increase was even more pronounce d 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 in crease in PLC activity in alpha (q)*44h mice with and without DCM was compa rable. 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 modifyin g factors and potential environmental influences in DCM. (C) 2001 Academic Press.