© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Altered cAMP-mediated signalling and its role in the pathogenesis of dilated cardiomyopathy
Cardiology Section, VA Salt Lake City Health Care System, Departments of Internal Medicine (Cardiology) and Pharmacology, University of Utah, 500 Foothill Boulevard, Salt Lake City, UT 84148, USA
* Tel.: +1-801-582-1565x4156; fax: +1-801-584-2532. Email address: matthew.movsesian{at}hsc.utah.edu
Alterations in the level and function of proteins involved in cAMP-mediated signalling are important in the pathophysiology and treatment of dilated cardiomyopathy. What is unclear is the extent to which these alterations, which attenuate receptor-stimulated cAMP generation, contribute to the pathogenesis of dilated cardiomyopathy and the extent to which they constitute a beneficial compensatory response. Studies in animals involving overexpression and ablation of proteins or peptides involved in cAMP-mediated signalling have yielded disparate results that are difficult to reconcile with a simple hypothesis. Our ability to understand these differences is limited by the lack of information on how these different genetic manipulations affect the phosphorylation of individual substrates of protein kinase A (PK-A) through which cAMP signals are transduced. This is important in view of evidence that the phosphorylation of individual PK-A substrates can be regulated selectively in different intracellular compartments, and that the phosphorylation of some PK-A substrates is increased in dilated cardiomyopathy while the phosphorylation of others is reduced. Approaches that quantify changes in the phosphorylation of individual PK-A substrates in models of dilated cardiomyopathy will provide information that may allow a better understanding of the pathogenesis of the syndrome and a more rational approach to its treatment.
KEYWORDS Altered cAMP-mediated signalling; Dilated cardiomyopathy; Protein kinase A