Circulation. 2003;108:736-740
Published online before print July 21, 2003, doi: 10.1161/01.CIR.0000084503.91330.49
Published online before print July 21, 2003, doi: 10.1161/01.CIR.0000084503.91330.49
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(Circulation. 2003;108:736.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Resistin Promotes Endothelial Cell Activation
Further Evidence of Adipokine-Endothelial Interaction
From the Division of Cardiac Surgery, Toronto General Hospital, University of Toronto, Toronto, Canada.
Correspondence to Subodh Verma, MD, PhD, Division of Cardiac Surgery, Toronto General Hospital, 14EN-215, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4. E-mail subodh.verma{at}sympatico.ca
Received December 12, 2002; de novo received June 11, 2003; accepted June 19, 2003.
Background— Adipocyte-derived hormones may represent a mechanism linking insulin resistance to cardiovascular disease. In the present study, we evaluated the direct effects of resistin, a novel adipocyte-derived hormone, on endothelial activation.
Methods and Results— Endothelial cells (ECs) were incubated with human recombinant resistin (10 to 100 ng/ML, 24 hours), and endothelin-1 (ET-1) release, ET-1 mRNA expression, and nitric oxide (NO) production were assessed. Transient transfection assays were used to evaluate the effects of resistin on transcription of human ET-1 gene promoter. Furthermore, the effects of resistin on AP-1–mutated ET-1 promoter were evaluated. The effects of resistin on expression of vascular cell adhesion molecule (VCAM-1) and monocyte chemoattractant chemokine (MCP-1) were studied in addition to CD40 receptor, CD40 ligand–induced MCP-1 expression, and tumor necrosis factor receptor–associated factor-3 (TRAF3), an inhibitor of CD40 signaling. Incubation of ECs with resistin resulted in an increase in ET-1 release and ET-1 mRNA expression, with no change in NO production. Whereas treatment with resistin resulted in an increase in ET-1 promoter activity, the AP-1–mutated promoter was inactive after resistin stimulation. Additionally, resistin-treated cells showed increased expression of VCAM-1 and MCP-1, with concomitant reductions in TRAF-3 expression. Resistin did not alter CD40 receptor expression; however, increased CD40 ligand induced MCP-1 production.
Conclusions— The novel adipokine resistin exerts direct effects to promote EC activation by promoting ET-1 release, in part by inducing ET-1 promoter activity via the AP-1 site. Furthermore, resistin upregulates adhesion molecules and chemokines and downregulates TRAF-3, an inhibitor of CD40 ligand signaling. In this fashion, resistin may be mechanistically linked to cardiovascular disease in the metabolic syndrome.
Key Words: endothelin • hormones • receptors
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