HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 289/1/H466    most recent 00170.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Brown, M. Articles by Jones, W. K. Search for Related Content PubMed PubMed Citation Articles by Brown, M. Articles by Jones, W. K.

Cardiac-specific blockade of NF-B in cardiac pathophysiology: differences between acute and chronic stimuli in vivo

Departments of ¹Pharmacology and Cell Biophysics and ²Pathology, and ³Division of Cardiology, University of Cincinnati, Ohio; and ⁴Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania

Submitted 24 February 2004 ; accepted in final form 27 January 2005

The role of NF-B in cardiac physiology and pathophysiology has been difficult to delineate due to the inability to specifically block NF-B signaling in the heart. Cardiac-specific transgenic models have recently been developed that repress NF-B activation by preventing phosphorylation at specific serine residues of the inhibitory B (IB) protein isoform IB. However, these models are unable to completely block NF-B because of a second signaling pathway that regulates NF-B function via Tyr42 phosphorylation of IB. We report the development of transgenic (3M) mouse lines that express the mutant IB^{(S32A,S36A,Y42F)} in a cardiac-specific manner. NF-B activation in cardiomyopathic TNF-1.6 mice is completely blocked by the 3M transgene but only partially blocked (70–80%) by the previously described double-mutant 2M [IB^(S32A,S36A)] transgene, which demonstrates the action of two proximal pathways for NF-B activation in TNF--induced cardiomyopathy. In contrast, after acute stimuli including administration of TNF- and ischemia-reperfusion (I/R), NF-B activation is blocked in both 2M and 3M transgenic mice. This result suggests that phosphorylation of the regulatory Ser32 and Ser36 predominantly mediates NF-B activation in these situations. We show that infarct size after I/R is reduced by 70% in 3M transgenic mice, which conclusively demonstrates that NF-B is involved in I/R injury. In summary, we have engineered novel transgenic mice that allow us to distinguish two major proximal pathways for NF-B activation. Our results demonstrate that the serine and tyrosine phosphorylation pathways are differentially activated during different pathophysiological processes (cardiomyopathy and I/R injury) and that NF-B contributes to infarct development after I/R.

nuclear factor-B; tumor necrosis factor-; signal transduction; ischemia-reperfusion

This article has been cited by other articles:

				M. Yang, J. Wu, C. M. Martin, P. R. Kvietys, and T. Rui Important role of p38 MAP kinase/NF-{kappa}B signaling pathway in the sepsis-induced conversion of cardiac myocytes to a proinflammatory phenotype Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H994 - H1001. [Abstract] [Full Text] [PDF]

				S. Kawano, T. Kubota, Y. Monden, T. Tsutsumi, T. Inoue, N. Kawamura, H. Tsutsui, and K. Sunagawa Blockade of NF-{kappa}B improves cardiac function and survival after myocardial infarction Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1337 - H1344. [Abstract] [Full Text] [PDF]

				Y. Higuchi, T. O. Chan, M. A. Brown, J. Zhang, B. R. DeGeorge Jr., H. Funakoshi, G. Gibson, C. F. McTiernan, T. Kubota, W. K. Jones, et al. Cardioprotection afforded by NF-{kappa}B ablation is associated with activation of Akt in mice overexpressing TNF-{alpha} Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H590 - H598. [Abstract] [Full Text] [PDF]