title: Globular adiponectin counteracts VCAM-1-mediated monocyte adhesion via AdipoR1/NF-κB/COX-2 signaling in human aortic endothelial cells.
abstract: Adiponectin (Ad) is an insulin-sensitizing adipocytokine with anti-inflammatory and vasoprotective properties. Cleavage of native full-length Ad (fAd) by elastases from activated monocytes generates globular Ad (gAd). Increased gAd levels are observed in the proximity of atherosclerotic lesions, but the physiological meaning of this proteolytic Ad fragment in the cardiovascular system is controversial. We compared molecular and biological properties of fAd and gAd in human aortic endothelial cells (HAEC). In control HAEC, both fAd and gAd acutely stimulated nitric oxide (NO) production by AMPK-dependent pathways. With respect to fAd, gAd more efficiently increased activation of NF-κB signaling pathways, resulting in cyclooxygenase-2 (COX-2) overexpression and COX-2-dependent prostacyclin 2 (PGI(2)) release. In contrast with fAd, gAd also increased p38 MAPK phosphorylation and VCAM-1 expression, ultimately enhancing adhesion of monocytes to endothelial cells. In HAEC lacking AdipoR1 (by siRNA), both activation of NF-κB as well as COX-2 overexpression by gAd were abrogated. Conversely, gAd-mediated p38MAPK activation and VCAM-1 expression were unaffected, and monocyte adhesion was greatly enhanced. In HAEC lacking COX-2 (by siRNA), reduced levels of PGI(2) further increased gAd-dependent monocyte adhesion. Our findings suggest that biological activities of fAd and gAd in endothelium do not completely overlap, with gAd possessing both AdipoR1-dependent ability to stimulate COX-2 expression and AdipoR1-independent effects related to expression of VCAM-1 and adhesion of monocytes to endothelium.
authors: Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy.
authors: Francesco
authors: F
authors: Addabbo
authors: Carmela
authors: C
authors: Nacci
authors: Leonarda
authors: L
authors: De Benedictis
authors: Valentina
authors: V
authors: Leo
authors: Mariela
authors: M
authors: Tarquinio
authors: Michael J
authors: MJ
authors: Quon
authors: Monica
authors: M
authors: Montagnani
mesh_terms: D052242:Adiponectin / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology; D001011:Aorta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004336:Drug Antagonism; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017510:Protein Folding; D034741:RNA, Small Interfering / Q000494:pharmacology; D054419:Receptors, Adiponectin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000494:pharmacology* / Q000502:physiology
chemical_list: C475418:ADIPOR1 protein, human; D052242:Adiponectin; D016328:NF-kappa B; D034741:RNA, Small Interfering; D054419:Receptors, Adiponectin; D019010:Vascular Cell Adhesion Molecule-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human