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Chromogranin A protects vessels against tumor necrosis factor alpha-induced vascular leakage.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2004 Mar; Vol. 18 (3), pp. 554-6. Date of Electronic Publication: 2004 Jan 20. - Publication Year :
- 2004
-
Abstract
- Elevated levels of circulating chromogranin A (CgA), a protein stored in the secretory granules of many neuroendocrine cells and neurons, have been detected in the blood of patients with neuroendocrine tumors or heart failure. The pathophysiological role of increased secretion of CgA is unknown. Using mice bearing subcutaneous tumors genetically engineered to secrete CgA in circulation, we have found that increased blood levels of this protein prevent vascular leakage induced by tumor necrosis factor-alpha (TNF) in the liver venous system. Structure-activity studies, carried out with CgA fragments administered to normal mice, showed that an active site is located within residues 7-57 of CgA. Accordingly, an anti-CgA antibody directed to residues 53-57 inhibited the effect of circulating CgA, either endogenously produced or exogenously administered, on liver vessels. Studies of the mechanism of action showed that CgA inhibits TNF-induced VE-cadherin down-regulation and barrier alteration of cultured endothelial cells, in an indirect manner. Other effectors, such as thrombin and vascular endothelial growth factor were partially inhibited by CgA N-terminal fragments in in vitro permeability assays. These findings suggest that circulating CgA could help regulate the endothelial barrier function and to protect vessels against TNF-induced plasma leakage in pathological conditions characterized by increased production of TNF and CgA, such as cancer or heart failure.
- Subjects :
- Animals
Antibodies, Monoclonal pharmacology
Antigens, CD
Binding Sites
Cadherins physiology
Capillary Leak Syndrome chemically induced
Capillary Permeability physiology
Cells, Cultured drug effects
Chromogranin A
Chromogranins chemistry
Chromogranins genetics
Chromogranins pharmacology
Endothelium, Vascular cytology
Extravasation of Diagnostic and Therapeutic Materials prevention & control
Female
Heart Failure physiopathology
Humans
Liver Circulation drug effects
Lymphoma metabolism
Lymphoma pathology
Mice
Mice, Nude
Neoplasm Transplantation
Neoplasms physiopathology
Peptide Fragments pharmacology
Protein Precursors metabolism
Protein Structure, Tertiary
Recombinant Fusion Proteins physiology
Thrombin antagonists & inhibitors
Vascular Endothelial Growth Factor A antagonists & inhibitors
Capillary Leak Syndrome prevention & control
Capillary Permeability drug effects
Chromogranins physiology
Tumor Necrosis Factor-alpha toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 18
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 14734634
- Full Text :
- https://doi.org/10.1096/fj.03-0922fje