Resistin Regulates Inflammatory Adhesion Molecules by Disassembling CAP1-Adenylyl Cyclase-Caveolin Complex in Human Endothelial Cells

Abstract

Resistin has been anticipated as a promising biomarker that could integrate metabolic disease and inflammatory disease. Resistin, first discovered as an adipokine, is often increased in patients with obesity and -inflammation. Due to increased level of resistin often corresponds to symptoms like insulin resistance and atherosclerosis, it is expected to be a linker that bridges the gap between metabolic disease and inflammation. However, there has been a controversy on whether resistin directly triggers insulin resistance or vascular inflammation, and the certainty of its receptor. Especially the uncertainty of receptor has been a considerable obstacle to research a causal relation of resistin to insulin resistance or atherosclerosis, and lastly developing a resistin-targeted drug. In this regard, our recent observation that adenylyl cyclase associated protein1 (CAP1) functioned as receptor of human resistin, shed light on molecular mechanisms of resistin action. Here, we showed that CAP1 is also a functional receptor of human resistin in endothelial cells with the mechanism being distinguished from monocytes due to particularly caveolae-enriched environments. In monocytes, the predominant adenylyl cyclase isoform localized on normal plasma membrane and resistin directly activated adenylyl cyclase through CAP1. Perplexingly in endothelial cells, the predominant isoform localized on caveolae and resistin indirectly de-suppressed adenylyl cyclase by disassembling CAP1-adenylyl cyclase-caveolin complex. Indeed CAP1 made an assembly with caveolin and adenylyl cyclase at normal state in human endothelial cells and the assembly was disorganized upon resistin treatment, leading to activation of cAMP-PKA-CREB signaling and NF-κB signaling pathway followed by overexpression of inflammatory adhesion molecules such as ICAM-1 and VCAM-1. Finally, we demonstrated these increased ICAM-1 and VCAM-1 effectively stimulated trans-endothelial migration of monocytes. Our findings revealed the new molecular mechanism on how resistin interacts with CAP1 and activates adenylyl cyclase in endothelial cells and consequently contributes to leukocyte infiltration.