Year: 2004
Type: article
Abstract: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the developed world.One form of CVD, congestive heart failure, is often preceded by a pathologic hypertrophy of the heart and is predicted to become an increasing public health problem.In order to identify new targets for intervention in these processes, a great deal of investigation has been dedicated to elucidating the molecular regulatory circuits involved in the development of cardiac hypertrophy.Recently, signaling through the calcium-activated phosphatase calcineurin has been implicated as a necessary and sufficient mediator of cardiac hypertrophy in a variety of animal models.However, the downstream effectors necessary for calcineurin-induced hypertrophy have not been determined, and the exact spatiotemporal stimuli that activate this signaling pathway are still a matter of debate.Here, we present evidence that the transcription factor, nuclear factor of activated T cells (NFAT) plays a critical role in calcineurin-mediated cardiac hypertrophic signaling.Analysis of gene-targeted mice revealed that NFATc3 is necessary for a full response to angiotensin II, pressure-overload, or calcineurin-induced cardiac hypertrophy, while the related factor NFATc4 is dispensable for the same responses.In addition, analysis of transgenic mice carrying a NFAT reporter construct indicated that while cardiac NFAT activity increases in a delayed and sustained manner in response to pressure overload-induced pathologic hypertrophy and infarct-induced heart failure, three models of "physiologic" hypertrophy fail to increase reporter activity over control levels.Taken together, these results indicate that the calcineurin-NFAT signaling module may be adapted specifically for transducing pathologic signals into a hypertrophic response in the heart, and validate NFAT factors as potential therapeutic targets for intervention in a number of cardiovascular disease processes.Future work will focus on elucidating the upstream calcium sources that induce calcineurin-NFAT activation in the heart, as well as how this pathway interacts with other intracellular signal transducers to produce a coordinated hypertrophic response to pathologic stimuli. List of Figures and Tables
Author: Benjamin J. Wilkins
Institution: University of Cincinnati
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W2506340764