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Calcineurin-NFAT Signaling in Cardiac Hypertrophy: In Sickness and In Health?

Wilkins, Benjamin Joseph
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1088446389

Abstract Details

2004, PhD, University of Cincinnati, Medicine : Molecular and Developmental Biology.
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.
Jeffery Molkentin (Advisor)

Recommended Citations

Citations

  • Wilkins, B. J. (2004). Calcineurin-NFAT Signaling in Cardiac Hypertrophy: In Sickness and In Health? [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1088446389

    APA Style (7th edition)

  • Wilkins, Benjamin. Calcineurin-NFAT Signaling in Cardiac Hypertrophy: In Sickness and In Health? 2004. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1088446389.

    MLA Style (8th edition)

  • Wilkins, Benjamin. "Calcineurin-NFAT Signaling in Cardiac Hypertrophy: In Sickness and In Health?" Doctoral dissertation, University of Cincinnati, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1088446389

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.