Abstract 13041: Identification of a Human Resistin Receptor That Mediates Inflammatory Actions
Background: Resistin is an adipokine first identified as a mediator of insulin resistance in obese mice. In human, however, resistin mainly resides in peripheral blood mononuclear cells and aggravates atherosclerosis by stimulating monocytes to induce vascular inflammation. Nevertheless, the receptor and intracellular signaling of human resistin have not yet been clarified.
Methods and Results: Here, we identified adenylyl cyclase-associated protein 1 (CAP1) as a novel functional receptor for human resistin and clarified its intracellular signaling pathway to modulate inflammatory action of monocytes (Figure 1). The process to find the receptor using mFc-hResistin fusion protein was illustrated in Figure2. We found that human resistin directly binds to CAP1 in human monocytes to mediate up-regulation of intracellular cAMP concentration, PKA activity and NF-kB related transcription of inflammatory cytokines such as IL-6, TNFα. We cloned three different deletion mutants of human CAP1 and demonstrated that resistin binds to proline-rich SH3 binding domain of CAP1. Furthermore, Adenovirus-mediated over-expression of CAP1 in monocytes resulted in the increased cAMP, PKA and NF-kB activities by resistin, and these CAP1-over-expressed monocytes aggravated adipose tissue inflammation in humanized resistin mouse obesity model. In contrast, suppression of CAP1 expression by small-interfering RNA abrogated the resistin-mediated activity of monocytes both in vitro and in vivo.
Conclusions: CAP1 serves as the most important functional receptor for resistin and plays pivotal roles in the inflammatory actions of monocytes through cAMP dependent signaling pathway.
- © 2012 by American Heart Association, Inc.