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1 Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio, USA
2 Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
3 Division of Cardiology, Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
4 Department of Medicine, Jefferson Medical College, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: joneswk{at}uc.edu.
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 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 a mutant IBS32A,S36A,Y42F in a cardiac specific manner. NF-B activation in cardiomyopathic TNF1.6 mice is completely blocked by the 3M transgene, but only partially blocked (70-80%) by the previously described double mutant 2M (IBS32A,S36A) transgene, demonstrating 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 in vivo, NF-B activation is blocked in both the 2M and 3M transgenic mice. This result suggests that phosphorylation of the regulatory Ser32,36 predominantly mediates NF-B activation in these situations. We show that infarct size after I/R is reduced by 70% in 3M transgenic mice, conclusively demonstrating 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.
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