Signal Transduction in Atria and Ventricles of Mice With Transient Cardiac Expression of Activated G Protein αq

• Published in: Circulation research Vol. 85; no. 11; p. 1085
• Main Authors: Mende, U, Kagen, A, Meister, M, Neer, E J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 26-11-1999; Lippincott
• Subjects: Biological and medical sciences; Cardiology. Vascular system; Heart; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Medical sciences; Heart; Atrium; Transient response; Rodentia; Transgenic animal; Cardiovascular disease; Heart ventricle; Gene expression; Signal transduction; Vertebrata; Mammalia; Mouse; Heart disease; Circulatory system; Hypertrophy; G protein
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.85.11.1085

We recently showed that the transient expression of a hemagglutinin (HA) epitope–tagged, constitutively active mutant of the G protein αq subunit (HAαq*) in the hearts of transgenic mice is sufficient to induce cardiac hypertrophy and dilatation that continue to progress after HAαq* protein becomes undetectable. We demonstrated that the activity of phospholipase Cβ, the immediate downstream target of activated Gαq, is increased at 2 weeks, when HAαq* is expressed, but also at 10 weeks, when HAαq* is no longer detectable. This observation suggested that the transient HAαq* expression causes multiple, persistent changes in cellular signaling pathways. We now demonstrate changes in the level, activity, or both of several signaling components, including changes in the amount and hormone responsiveness of phospholipase Cβ enzymes, in the basal level of diacylglycerol (which predominantly reflects activation of phospholipase D), in the amount or distribution of protein kinase C (PKC) isoforms (PKCα, PKCδ, and PKCε), and in the amount of several endogenous G proteins. These changes vary depending on the isoform of the signaling molecule, the chamber in which it is expressed, and the presence or absence of HAαq*. Our results suggest that a network of linked signaling functions determines the development of hypertrophy. They also suggest that atria and ventricles represent different signaling domains. It is likely that such changes occur in other model systems in which the activity of a single signaling component is increased, either due to an activating mutation or due to overexpression of the wild type.