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Am J Physiol Endocrinol Metab (October 16, 2007). doi:10.1152/ajpendo.00115.2007
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Submitted on February 20, 2007
Accepted on October 5, 2007

Adiponectin Suppresses IkB Kinase Activation Induced by Tumor Necrosis Factor-{alpha} or High Glucose in Endothelial Cells: Role of cAMP and AMP Kinase Signaling

Xiangdong Wu1, Kalyankar Mahadev1, Lauren Fuchsel1, Raogo Ouedraogo1, Shi-qiong Xu1, and Barry J. Goldstein2*

1 Medicine (Endocrinology), Thomas Jefferson University, Philadelphia, Pennsylvania, United States
2 Medicine (Endocrinology), Thomas Jefferson University, Philadelphia, United States

* To whom correspondence should be addressed. E-mail: barry.goldstein{at}jefferson.edu.

Adiponectin is a protein secreted from adipocytes that exhibits salutary effects in the vascular endothelium by signaling mechanisms that are not well understood. In obesity-related disease states and type 2 diabetes, circulating substances, including tumor necrosis factor-{alpha} (TNF{alpha}) and high glucose, activate I{kappa}B kinase (IKK){beta} and reduce the abundance of its substrate, Inhibitor of {kappa}B (I{kappa}B){alpha}, leading to nuclear translocation of the transcription factor NF{kappa}B and stimulation of an inflammatory signaling cascade closely associated with endothelial dysfunction. The present study demonstrates that the globular domain of adiponectin (gAd) potently suppresses the activation of IKK{beta} by either TNF{alpha} or high glucose in human umbilical vein endothelial cells, and ameliorates the associated loss of I{kappa}B{alpha} protein. Interestingly, activation of AMP kinase was substantially more effective than cAMP signaling in suppressing high glucose-induced IKK{beta} activity, while both pathways were comparably active in suppressing the TNF{alpha}-induced increase in IKK{beta}. Both cAMP/protein kinase A signaling and activation of the AMP kinase pathway played a role in the suppression by gAd of TNF{alpha}and high glucose-mediated IKK{beta} activation. These findings support an important role for adiponectin in anti-inflammatory signaling in the endothelium and also imply that multiple pathways are involved in the cellular effects of adiponectin.




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