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J. Biol. Chem., Vol. 283, Issue 36, 24889-24898, September 5, 2008

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Adiponectin Blocks Interleukin-18-mediated Endothelial Cell Death via APPL1-dependent AMP-activated Protein Kinase (AMPK) Activation and IKK/NF-B/PTEN Suppression^*

Bysani Chandrasekar¹, William H. Boylston^¶, Kaliyamurthi Venkatachalam, Nicholas J. G. Webster^||, Sumanth D. Prabhu^**, and Anthony J. Valente

From the Department of Veterans Affairs South Texas Veterans Health Care System, San Antonio, Texas 78229, the Department of Medicine and ^¶Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229, the ^||Department of Medicine, University of California, San Diego, California 92093, and the ^**Institute of Molecular Cardiology, Department of Medicine, University of Louisville and Medical Service, Louisville Veterans Affairs Medical Center, Louisville, Kentucky 40292

The adipocyte-derived cytokine adiponectin is known to exert anti-inflammatory and anti-apoptotic effects. In patients with atherosclerotic cardiovascular disease, circulating levels of adiponectin correlate inversely with those of the proinflammatory, proapoptotic cytokine interleukin (IL)-18. The opposing actions of IL-18 and adiponectin on both cell survival and inflammation led us to investigate whether adiponectin signaling antagonizes IL-18-mediated endothelial cell death and to identify the underlying molecular mechanisms. Treatment with IL-18 suppressed Akt phosphorylation and its associated kinase activity, induced IB kinase (IKK)-NF-B-dependent PTEN activation, and promoted endothelial cell death. Pretreatment with adiponectin stimulated APPL1-dependent AMPK activation, reversed Akt inhibition in a phosphatidylinositol 3-kinase-dependent manner, blocked IKK-NF-B-PTEN signaling, reduced caspase-3 activity, blocked Bax translocation, and inhibited endothelial cell death. The cytoprotective effect of adiponectin signaling was recapitulated by treatment with the pharmacological AMPK activator 5-aminoimidazole-4-carboxamide-1-β-riboside. Collectively, these results demonstrated that adiponectin reverses IL-18-mediated endothelial cell death through an AMPK-associated mechanism, which may thus have therapeutic potential for diminishing IL-18-dependent vascular injury and inflammation.

Received for publication, June 2, 2008 , and in revised form, July 7, 2008.

^* This work was supported in part by the Research Service of the Department of Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Medicine/Cardiology, The University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-4598; Fax: 210-567-6960; E-mail: chandraseka{at}uthscsa.edu.

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