Cardiac-specific blockade of NF-kB in cardiac pathophysiology: Differences between acute and chronic stimuli in vivo
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 http://dx.doi.org/10.1152/ajpheart.00170.2004.
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 Â© 2005 the American Physiological Society.