Adiponectin suppresses IkappaB kinase activation induced by tumor necrosis factor-alpha or high glucose in endothelial cells: role of cAMP and AMP kinase signaling.
Adiponectin is a protein secreted from adipocytes that exhibits salutary effects in the vascular endothelium by signaling mechanisms that are not well understood. In obesity-related disease states and type 2 diabetes, circulating substances, including tumor necrosis factor-alpha (TNFalpha) and high glucose, activate IkappaB kinase (IKK)beta and reduce the abundance of its substrate, inhibitor of kappaB (IkappaB)alpha, leading to nuclear translocation of the transcription factor NF-kappaB and stimulation of an inflammatory signaling cascade closely associated with endothelial dysfunction. The present study demonstrates that the globular domain of adiponectin (gAd) potently suppresses the activation of IKKbeta by either TNFalpha or high glucose in human umbilical vein endothelial cells and ameliorates the associated loss of IkappaBalpha protein. Interestingly, activation of AMP kinase was substantially more effective than cAMP signaling in suppressing high glucose-induced IKKbeta activity, whereas both pathways were comparably active in suppressing the TNFalpha-induced increase in IKKbeta. Both cAMP/protein kinase A signaling and activation of the AMP kinase pathway played a role in the suppression by gAd of TNFalpha- and high glucose-mediated IKKbeta activation. These findings support an important role for adiponectin in anti-inflammatory signaling in the endothelium and also imply that multiple pathways are involved in the cellular effects of adiponectin.
Wu
Xiangdong
X
Dept. of Medicine, Jefferson Medical College, Suite 320 Curtis Bldg., 1015 Walnut St., Philadelphia, PA 19107, USA.
Mahadev
Kalyankar
K
Fuchsel
Lauren
L
Ouedraogo
Raogo
R
Xu
Shi-Qiong
SQ
Goldstein
Barry J
BJ
D055372:AMP-Activated Protein Kinases; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D052242:Adiponectin / Q000494:pharmacology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
C499918:ADIPOQ protein, human; D000067956:Adenylyl Cyclase Inhibitors; D052242:Adiponectin; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; C000606204:NFKBIA protein, human; D010446:Peptide Fragments; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D012265:Ribonucleotides; D014409:Tumor Necrosis Factor-alpha; C516138:dorsomorphin; D000072000:NF-KappaB Inhibitor alpha; D005576:Colforsin; D000620:Aminoimidazole Carboxamide; D016048:Dideoxyadenosine; C021008:2',5'-dideoxyadenosine; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D000262:Adenylyl Cyclases; C031143:AICA ribonucleotide; D005947:Glucose