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

M. Brown
Michael P. McGuinness, Philadelphia College of Osteopathic Medicine
T. Wright
X. Ren
Y. Wang
G. P. Boivin
H. Hahn
A. M. Feldman
W. K. Jones

This article was published in American Journal of Physiology - Heart and Circulatory Physiology, Volume 289, Issue 1 58-1, Pages H466-H476.

The published version is available at

Copyright © 2005 APS.


The role of NF-kB in cardiac physiology and pathophysiology has been difficult to delineate due to the inability to specifically block NF-kB signaling in the heart. Cardiac-specific transgenic models have recently been developed that repress NF-kB activation by preventing phosphorylation at specific serine residues of the inhibitory kB (IkB) protein isoform IkBα. However, these models are unable to completely block NF-kB because of a second signaling pathway that regulates NF-kB function via Tyr42 phosphorylation of IkBα. We report the development of transgenic (3M) mouse lines that express the mutant IkBα(S32A,S36A,Y42F) in a cardiac-specific manner. NF-kB 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 [IkBα(S32A,S36A)] transgene, which demonstrates the action of two proximal pathways for NF-kB activation in TNF-α-induced cardiomyopathy. In contrast, after acute stimuli including administration of TNF-α and ischemia-reperfusion (I/R), NF-kB activation is blocked in both 2M and 3M transgenic mice. This result suggests that phosphorylation of the regulatory Ser32 and Ser36 predominantly mediates NF-kB 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-kB 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-kB 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-kB contributes to infarct development after I/R. Copyright © 2005 the American Physiological Society.