Adiponectin antagonizes stimulatory effect of tumor necrosis factor-alpha on vascular smooth muscle cell calcification: regulation of growth arrest-specific gene 6-mediated survival pathway by adenosine 5'-monophosphate-activated protein kinase.
Adiponectin exhibits diverse protective effects against atherogenesis and antagonizes many effects of TNFalpha. Here, we investigated the effect of adiponectin and TNFalpha on vascular calcification, a critical event in the development and progression of vascular disease. In human aortic smooth muscle cells (HASMC), TNFalpha augmented inorganic phosphate (Pi)-induced calcification, whereas adiponectin significantly suppressed it and abolished the stimulatory effect of TNFalpha in a concentration-dependent manner. Similarly, adiponectin ameliorated the accelerating effect of TNFalpha on Pi-induced apoptosis, the essential process of HASMC calcification. Furthermore, these effects of TNFalpha and adiponectin were associated with AMP-activated protein kinase (AMPK)-dependent growth arrest-specific gene 6 (Gas6) expression and Akt signaling. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), induced phosphorylation of AMPK and significantly inhibited Pi-induced calcification in HASMC. Conversely, pharmacological inhibition of AMPK by compound C blocked both AMPK activation and the inhibitory effect of adiponectin on calcification, providing evidence that AMPK plays a regulatory role in vascular calcification. Reporter assay revealed that adiponectin restored Gas6 promoter activity decreased by TNFalpha, and the effect of adiponectin was abrogated by compound C. These results demonstrate that adiponectin antagonizes the stimulatory effect of TNFalpha on vascular calcification by restoration of the AMPK-dependent Gas6-mediated survival pathway.
Son
Bo-Kyung
BK
Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Akishita
Masahiro
M
Iijima
Katsuya
K
Kozaki
Koichi
K
Maemura
Koji
K
Eto
Masato
M
Ouchi
Yasuyoshi
Y
D055372:AMP-Activated Protein Kinases; D052242:Adiponectin / Q000494:pharmacology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002114:Calcinosis / Q000517:prevention & control*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D009097:Multienzyme Complexes / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D000099255:Growth Arrest-Specific Protein 6
D055372:AMP-Activated Protein Kinases; D052242:Adiponectin; D000620:Aminoimidazole Carboxamide; D036341:Intercellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D012265:Ribonucleotides; D014409:Tumor Necrosis Factor-alpha; D000099255:Growth Arrest-Specific Protein 6; C031143:AICA ribonucleotide