Dilated cardiomyopathy in two transgenic mouse lines expressing activated G protein alpha(q): lack of correlation between phospholipase C activation and the phenotype.

Abstract

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.

• Authors: U Mende, C Semsarian, D C Martins, A Kagen, C Duffy, F J Schoen, E J Neer
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 33 Issue 8 Pg. 1477-91 (Aug 2001) ISSN: 0022-2828 [Print] England
• PMID: 11448136 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2001 Academic Press.

Chemical References

• Isoenzymes
• Type C Phospholipases
• GTP-Binding Protein alpha Subunits, Gq-G11
• Heterotrimeric GTP-Binding Proteins

Topics

• Aging
• Animals
• Blotting, Western
• Cardiomyopathy, Dilated (genetics, metabolism)
• Enzyme Activation
• GTP-Binding Protein alpha Subunits, Gq-G11
• Heart Ventricles
• Heterotrimeric GTP-Binding Proteins (metabolism)
• Isoenzymes (metabolism)
• Mice
• Mice, Transgenic
• Phenotype
• Signal Transduction
• Time Factors
• Type C Phospholipases (biosynthesis)