Dilated Cardiomyopathy in Two Transgenic Mouse Lines Expressing Activated G Protein αq: Lack of Correlation Between Phospholipase C Activation and the Phenotype

We previously described a transgenic mouse line (αq*52) in which cardiac-specific expression of activated G αqprotein (HA αq*) leads to activation of phospholipase C β (PLC β), the immediate downstream target of HAαq *, with subsequent development of cardiac hypertrophy and dilation. We now describe a second, independent line in the same genetic background (αq*44h) with lower expression of HAαq * 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% ofαq *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 αq*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 αq*44h mice with and without DCM was comparable. Thus, the delayed time course inαq *44h mice unmasked a lack of correlation between PLC activation and development of DCM in response to HA αq* 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.