Lim domain binding 2: a key driver of transendothelial migration of leukocytes and atherosclerosis.
Arterioscler Thromb Vasc Biol
; 34(9): 2068-77, 2014 Sep.
Article
in En
| MEDLINE
| ID: mdl-24925974
ABSTRACT
OBJECTIVE:
Using a multi-tissue, genome-wide gene expression approach, we recently identified a gene module linked to the extent of human atherosclerosis. This atherosclerosis module was enriched with inherited risk for coronary and carotid artery disease (CAD) and overlapped with genes in the transendothelial migration of leukocyte (TEML) pathway. Among the atherosclerosis module genes, the transcription cofactor Lim domain binding 2 (LDB2) was the most connected in a CAD vascular wall regulatory gene network. Here, we used human genomics and atherosclerosis-prone mice to evaluate the possible role of LDB2 in TEML and atherosclerosis. APPROACH ANDRESULTS:
mRNA profiles generated from blood macrophages in patients with CAD were used to infer transcription factor regulatory gene networks; Ldlr(-/-)Apob(100/100) mice were used to study the effects of Ldb2 deficiency on TEML activity and atherogenesis. LDB2 was the most connected gene in a transcription factor regulatory network inferred from TEML and atherosclerosis module genes in CAD macrophages. In Ldlr(-/-)Apob(100/100) mice, loss of Ldb2 increased atherosclerotic lesion size ≈2-fold and decreased plaque stability. The exacerbated atherosclerosis was caused by increased TEML activity, as demonstrated in air-pouch and retinal vasculature models in vivo, by ex vivo perfusion of primary leukocytes, and by leukocyte migration in vitro. In THP1 cells, migration was increased by overexpression and decreased by small interfering RNA inhibition of LDB2. A functional LDB2 variant (rs10939673) was associated with the risk and extent of CAD across several cohorts.CONCLUSIONS:
As a key driver of the TEML pathway in CAD macrophages, LDB2 is a novel candidate to target CAD by inhibiting the overall activity of TEML.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transcription Factors
/
Coronary Artery Disease
/
Carotid Artery Diseases
/
Chemotaxis, Leukocyte
/
Atherosclerosis
/
Transendothelial and Transepithelial Migration
/
LIM Domain Proteins
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Arterioscler Thromb Vasc Biol
Journal subject:
ANGIOLOGIA
Year:
2014
Type:
Article