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Diabetes Publish Ahead of Print published online ahead of print February 7, 2007
DOI: 10.2337/db06-1580
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Original Research

Adiponectin-induced eNOS activation and Nitric Oxide Production are Mediated by APPL1 in Endothelial Cells

Kenneth K Y Cheng1,,2, Karen S L Lam1,,2, Yu Wang3, Huang Yu4, David Carling5, Donghai Wu6, Chiwai Wong6, and Aimin Xu1,,2

1Department of Medicine, University of Hong Kong, China
2Research Center of Heart, Brain Hormone and Healthy Aging, University of Hong Kong, China
3Genome Research Center and Department of Biochemistry, University of Hong Kong, China
4Department of Physiology, Chinese University of Hong Kong
5Cellular Stress Group, MRC Clinical Sciences Centre, Imperial College, UK
6Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, China

Correspondence: amxu{at}hkucc.hku.hk

Adiponectin protects the vascular system partly through stimulation of endothelial nitric oxide (NO) production and endothelium-dependent vasodilation. The present study investigated the role of the two recently identified adiponectin receptors (AdipoR1 and AdipoR2) and their downstream effectors in mediating the endothelium actions of adiponectin. In human umbilical vein endothelial cells (HUVECs), adiponectin-induced phosphorylation of eNOS at Ser1177 and NO production were abrogated when expression of adipoR1 and adipoR2 was simultaneously suppressed. The proteomic analysis demonstrated that the cytoplasmic tails of both adipoR1 and adipoR2 interacted with APPL1, an adaptor protein that contains pleckstrin homology domain, phosphotyrosine-binding domain and a leucine zipper motif. Suppression of APPL1 expression by RNAi significantly attenuated adiponectin-induced phosphorylation of AMP-activated protein kinase (AMPK) at Thr172 and eNOS at Ser1177, and the complex formation between eNOS and heat shock protein (HSP) 90, resulting in a marked reduction of NO production. Adenovirus-mediated overexpression of a constitutively active version of AMPK reversed these changes. In db/db diabetic mice, both APPL1 expression and adiponectin-induced vasodilation were significantly decreased compared with those in their lean littermates. Taken together, these results suggest that APPL1 acts as a common downstream effector of adipoR1 and adipoR2 mediating adiponectin-evoked endothelial NO production and endothelium-dependent vasodilation.


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