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Adiponectin-Induced Endothelial Nitric Oxide Synthase Activation and Nitric Oxide Production Are Mediated by APPL1 in Endothelial Cells

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

Address correspondence and reprint requests to Aimin Xu, PhD, Department of Medicine, University of Hong Kong, L8-43, New Laboratory Block, 21 Sassoon Road, Hong Kong. E-mail: amxu{at}hkucc.hku.hk

Abbreviations: AMPK, AMP-activated protein kinase; eNOS, endothelial nitric oxide synthase; GFP, green fluorescent protein; HSP, heat shock protein; HUVEC, human umbilical vein endothelial cell; L-NAME, N-nitro-L-arginine methyl ester; PI, phosphoinositide; RNAi, RNA interference

Adiponectin protects the vascular system partly through stimulation of endothelial nitric oxide (NO) production and endothelium-dependent vasodilation. The current study investigated the role of two recently identified adiponectin receptors, AdipoR1 and -R2, and their downstream effectors in mediating the endothelium actions of adiponectin. In human umbilical vein endothelial cells, adiponectin-induced phosphorylation of endothelial NO synthase (eNOS) at Ser¹¹⁷⁷ and NO production were abrogated when expression of AdipoR1 and -R2 were simultaneously suppressed. Proteomic analysis demonstrated that the cytoplasmic tails of both AdipoR1 and -R2 interacted with APPL1, an adaptor protein that contains a PH (pleckstrin homology) domain, a PTB (phosphotyrosine-binding) domain, and a Leucine zipper motif. Suppression of APPL1 expression by RNA interference 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 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 their lean littermates. Taken together, these results suggest that APPL1 acts as a common downstream effector of AdipoR1 and -R2, mediating adiponectin-evoked endothelial NO production and endothelium-dependent vasodilation.

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