AJP - Heart Calcium Transients and Cell-Sarcomere
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 293: H1877-H1882, 2007. First published July 6, 2007; doi:10.1152/ajpheart.00516.2007
0363-6135/07 $8.00
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/3/H1877    most recent
00516.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Huggins, G. S.
Right arrow Articles by Reed, G. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Huggins, G. S.
Right arrow Articles by Reed, G. L.

The CREB leucine zipper regulates CREB phosphorylation, cardiomyopathy, and lethality in a transgenic model of heart failure

Gordon S. Huggins,1 John J. Lepore,2 Sarah Greytak,1 Richard Patten,1 Rachel McNamee,3 Mark Aronovitz,1 Paul J. Wang,4 and Guy L. Reed3

1Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts; 2GlaxoSmithKline, King of Prussia, Pennsylvania; 3Medical College of Georgia, Augusta, Georgia; and 4Stanford University Medical Center, Stanford, California

Submitted 30 April 2007 ; accepted in final form 24 June 2007

Signaling through cAMP plays an important role in heart failure. Phosphorylation of cAMP response element binding protein (CREB) at serine-133 regulates gene expression in the heart. We examined the functional significance of CREB-S133 phosphorylation by comparing transgenic models in which a phosphorylation resistant CREB-S133A mutant containing either an intact or a mutated leucine zipper domain (CREB-S133A-LZ) was expressed in the heart. In vitro, CREB-S133A retained the ability to interact with wild-type CREB, whereas CREB-S133A-LZ did not. In vivo, CREB-S133A and CREB-S133A-LZ were expressed at comparable levels in the heart; however, CREB-S133A markedly suppressed the phosphorylation of endogenous CREB, whereas CREB-S133A-LZ had no effect. The one-year survival of mice from two CREB-S133A-LZ transgenic lines was equivalent to nontransgenic littermate control mice (NTG), whereas transgenic CREB-S133A mice died with heart failure at a median 30 wk of age (P < 0.0001). CREB-S133A mice had an altered gene expression characteristic of the failing heart, whereas CREB-S133A-LZ mice did not. Left ventricular contractile function was substantially reduced in CREB-S133A mice versus NTG mice and only modestly reduced in CREB-S133A-LZ mice (P < 0.02). When considered in light of other studies, these findings indicate that overexpression of the CREB leucine zipper is required for both inhibition of endogenous CREB phosphorylation and cardiomyopathy in this murine model of heart failure.

adenosine 3',5'-cyclic monophosphate responsive element binding protein


Address for reprint requests and other correspondence: G. S. Huggins, MCRI Ctr. for Translational Genomics, Tufts-New England Medical Ctr., 750 Washington St., Boston, MA 02111 (e-mail: ghuggins{at}tufts-nemc.org)






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.