Mechanism and Role of High Density Lipoprotein-induced Activation of AMP-activated Protein Kinase in Endothelial Cells

• Published in: The Journal of biological chemistry 2010-02, Vol.285 (7), p.4387-4397
• Main Authors: Kimura, Takao, Tomura, Hideaki, Sato, Koichi, Ito, Masaaki, Matsuoka, Isao, Im, Doon-Soon, Kuwabara, Atsushi, Mogi, Chihiro, Itoh, Hiroshi, Kurose, Hitoshi, Murakami, Masami, Okajima, Fumikazu
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Aorta - cytology; Aorta - metabolism; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinase Kinase - genetics; Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism; Cell Adhesion - genetics; Cell Adhesion - physiology; Cell Line; Cell Proliferation; Cytokines/Tumor Necrosis Factor; Diseases/Atherosclerosis; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Endothelial Cells - metabolism; Enzyme Activation - drug effects; G Proteins/Coupled Receptors (GPCR); Humans; In Vitro Techniques; Lipid/Phospholipid; Lipoprotein/HDL; Lipoproteins, HDL - pharmacology; Male; Mice; Phosphorylation - drug effects; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors, Lysosphingolipid - genetics; Receptors, Lysosphingolipid - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Scavenger Receptors, Class B - genetics; Scavenger Receptors, Class B - metabolism; Signal Transduction; Signal Transduction/Protein Kinases; Umbilical Veins - cytology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.043869

The upstream signaling pathway leading to the activation of AMP-activated protein kinase (AMPK) by high density lipoprotein (HDL) and the role of AMPK in HDL-induced antiatherogenic actions were investigated. Experiments using genetic and pharmacological tools showed that HDL-induced activation of AMPK is dependent on both sphingosine 1-phosphate receptors and scavenger receptor class B type I through calcium/calmodulin-dependent protein kinase kinase and, for scavenger receptor class B type I system, additionally serine-threonine kinase LKB1 in human umbilical vein endothelial cells. HDL-induced activation of Akt and endothelial NO synthase, stimulation of migration, and inhibition of monocyte adhesion and adhesion molecule expression were dependent on AMPK activation. The inhibitory role of AMPK in the adhesion molecule expression and monocyte adhesion on endothelium of mouse aorta was confirmed in vivo and ex vivo. On the other hand, stimulation of ERK and proliferation were hardly affected by AMPK knockdown but completely inhibited by an N17Ras, whereas the dominant-negative Ras was ineffective for AMPK activation. In conclusion, dual HDL receptor systems differentially regulate AMPK activity through calcium/calmodulin-dependent protein kinase kinase and/or LKB1. Several HDL-induced antiatherogenic actions are regulated by AMPK, but proliferation-related actions are regulated by Ras rather than AMPK.