PMID- 20624982
OWN - NLM
STAT- MEDLINE
DCOM- 20100927
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 107
IP  - 30
DP  - 2010 Jul 27
TI  - MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible 
      endothelium in vivo and in vitro.
PG  - 13450-5
LID - 10.1073/pnas.1002120107 [doi]
AB  - A chronic proinflammatory state precedes pathological change in arterial 
      endothelial cells located within regions of susceptibility to atherosclerosis. 
      The potential contributions of regulatory microRNAs to this disequilibrium were 
      investigated by artery site-specific profiling in normal adult swine. Expression 
      of endothelial microRNA10a (miR-10a) was lower in the athero-susceptible regions 
      of the inner aortic arch and aorto-renal branches than elsewhere. Expression of 
      Homeobox A1 (HOXA1), a known miR-10a target, was up-regulated in the same 
      locations. Endothelial transcriptome microarray analysis of miR-10a knockdown in 
      cultured human aortic endothelial cells (HAEC) identified 
      IkappaB/NF-kappaB-mediated inflammation as the top category of up-regulated 
      biological processes. Phosphorylation of IkappaBalpha, a prerequisite for 
      IkappaBalpha proteolysis and NF-kappaB activation, was significantly up-regulated 
      in miR-10a knockdown HAEC and was accompanied by increased nuclear expression of 
      NF-kappaB p65. The inflammatory biomarkers monocyte chemotactic protein 1 
      (MCP-1), IL-6, IL-8, vascular cell adhesion molecule 1 (VCAM-1), and E-selectin 
      were elevated following miR-10a knockdown. Conversely, knockin of miR-10a (a 
      conservative 25-fold increase) inhibited the basal expression of VCAM-1 and 
      E-selectin in HAEC. Two key regulators of IkappaBalpha 
      degradation--mitogen-activated kinase kinase kinase 7 (MAP3K7; TAK1) and 
      beta-transducin repeat-containing gene (betaTRC)--contain a highly conserved 
      miR-10a binding site in the 3' UTR. Both molecules were up-regulated by miR-10a 
      knockdown and suppressed by miR-10a knockin, and evidence of direct miR-10a 
      binding to the 3' UTR was demonstrated by luciferase assay. Comparative 
      expression studies of endothelium located in athero-susceptible aortic arch and 
      athero-protected descending thoracic aorta identified significantly up-regulated 
      MAP3K7, betaTRC, phopho-IkappaBalpha, and nuclear p65 expression suggesting that 
      the differential expression of miR-10a contributes to the regulation of 
      proinflammatory endothelial phenotypes in athero-susceptible regions in vivo.
FAU - Fang, Yun
AU  - Fang Y
AD  - Institute for Medicine and Engineering, Center for Bioinformatics, and Department 
      of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Shi, Congzhu
AU  - Shi C
FAU - Manduchi, Elisabetta
AU  - Manduchi E
FAU - Civelek, Mete
AU  - Civelek M
FAU - Davies, Peter F
AU  - Davies PF
LA  - eng
GR  - P01 HL062250/HL/NHLBI NIH HHS/United States
GR  - HL62250/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100712
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (BTRC protein, human)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (MicroRNAs)
RN  - 0 (NF-kappa B)
RN  - 0 (NFKBIA protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (beta-Transducin Repeat-Containing Proteins)
RN  - 0 (homeobox A1 protein)
RN  - 139874-52-5 (NF-KappaB Inhibitor alpha)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - EC 2.7.11.25 (MAP kinase kinase kinase 7)
SB  - IM
MH  - Animals
MH  - Aorta, Thoracic/metabolism/pathology
MH  - Atherosclerosis/genetics
MH  - Blotting, Western
MH  - Cell Line
MH  - Cells, Cultured
MH  - Endothelial Cells/metabolism/pathology
MH  - Endothelium/*metabolism/pathology
MH  - *Gene Expression Profiling
MH  - Gene Knockdown Techniques
MH  - Genetic Predisposition to Disease
MH  - Homeodomain Proteins/genetics/metabolism
MH  - Humans
MH  - I-kappa B Proteins/metabolism
MH  - In Situ Hybridization, Fluorescence
MH  - Inflammation/genetics
MH  - MAP Kinase Kinase Kinases/genetics/metabolism
MH  - MicroRNAs/*genetics/metabolism
MH  - NF-KappaB Inhibitor alpha
MH  - NF-kappa B/metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - Phenotype
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Swine
MH  - Transcription Factors/genetics/metabolism
MH  - beta-Transducin Repeat-Containing Proteins/genetics/metabolism
PMC - PMC2922125
COIS- The authors declare no conflict of interest.
EDAT- 2010/07/14 06:00
MHDA- 2010/09/29 06:00
PMCR- 2010/07/12
CRDT- 2010/07/14 06:00
PHST- 2010/07/14 06:00 [entrez]
PHST- 2010/07/14 06:00 [pubmed]
PHST- 2010/09/29 06:00 [medline]
PHST- 2010/07/12 00:00 [pmc-release]
AID - 1002120107 [pii]
AID - 201002120 [pii]
AID - 10.1073/pnas.1002120107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13450-5. doi: 
      10.1073/pnas.1002120107. Epub 2010 Jul 12.