Document Detail


Adropin is a novel regulator of endothelial function.
MedLine Citation:
PMID:  20837912     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Adropin is a recently identified protein that has been implicated in the maintenance of energy homeostasis and insulin resistance. Because vascular function and insulin sensitivity are closely related, we hypothesized that adropin may also exert direct effects on the endothelium.
METHODS AND RESULTS: In vitro cell culture models were partnered with an in vivo murine injury model to determine the potential vascular effects of adropin. Adropin was expressed in human umbilical vein and coronary artery endothelial cells (ECs). Adropin-treated endothelial cells exhibited greater proliferation, migration and capillary-like tube formation and less permeability and tumor necrosis factor-α-induced apoptosis. In keeping with a vascular protective effect, adropin stimulated Akt Ser(473) and endothelial nitric oxide (NO) synthase Ser(1177) phosphorylation. The former was abrogated in the presence of the phosphatidylinositol 3-kinase inhibitor LY294002, whereas the latter was attenuated by LY294002 and by mitogen-activated protein kinase kinase 1 inhibition with PD98059. Together, these findings suggest that adropin regulates NO bioavailability and events via the phosphatidylinositol 3-kinase-Akt and extracellular signal regulated kinase 1/2 signaling pathways. Adropin markedly upregulated vascular endothelial growth factor receptor-2 (VEGFR2) transcript and protein levels, and in VEGFR2-silenced endothelial cells, adropin failed to induce phosphorylation of endothelial NO synthase, Akt, and extracellular signal regulated kinase 1/2, supporting VEGFR2 as an upstream target of adropin-mediated endothelial NO synthase activation. Last, adropin improved murine limb perfusion and elevated capillary density following induction of hindlimb ischemia.
CONCLUSIONS: We report a potential endothelial protective role of adropin that is likely mediated via upregulation of endothelial NO synthase expression through the VEGFR2-phosphatidylinositol 3-kinase-Akt and VEGFR2-extracellular signal regulated kinase 1/2 pathways. Adropin represents a novel target to limit diseases characterized by endothelial dysfunction in addition to its favorable metabolic profile.
Authors:
Fina Lovren; Yi Pan; Adrian Quan; Krishna K Singh; Praphulla C Shukla; Milan Gupta; Mohammed Al-Omran; Hwee Teoh; Subodh Verma
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  122     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-14     Completed Date:  2010-10-01     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  S185-92     Citation Subset:  AIM; IM    
Affiliation:
Division of Cardiac Surgery, St. Michael's Hospital, Toronto, Ontario, Canada.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects,  genetics
Cell Movement*
Cell Proliferation*
Cells, Cultured
Chromones / pharmacology
Endothelial Cells / metabolism*
Enzyme Inhibitors / pharmacology
Flavonoids / pharmacology
Gene Expression Regulation*
Gene Silencing
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors,  genetics,  metabolism
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors,  genetics,  metabolism
Morpholines / pharmacology
Nitric Oxide Synthase Type III / genetics,  metabolism
Phosphatidylinositol 3-Kinases / antagonists & inhibitors,  genetics,  metabolism
Phosphorylation / drug effects,  genetics
Proteins / genetics,  metabolism*
Proto-Oncogene Proteins c-akt / genetics,  metabolism
RNA, Messenger / biosynthesis,  genetics
Tumor Necrosis Factor-alpha / genetics,  metabolism
Vascular Endothelial Growth Factor Receptor-2 / biosynthesis,  genetics
Grant Support
ID/Acronym/Agency:
//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; 0/Chromones; 0/Enho protein, mouse; 0/Enzyme Inhibitors; 0/Flavonoids; 0/Morpholines; 0/Proteins; 0/RNA, Messenger; 0/Tumor Necrosis Factor-alpha; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; EC 1.14.13.39/NOS3 protein, human; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, mouse; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/MAPK1 protein, human; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3

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