Bicuspid aortic valve (BAV) is a common congenital heart defect
(population incidence, 1–2%)
1
–
3
that
frequently presents with ascending aortic aneurysm (AscAA)
4
. BAV/AscAA shows autosomal dominant
inheritance with incomplete penetrance and male predominance. Causative gene
mutations are known for ≤1% of nonsyndromic BAV cases with/without AscAA
(e.g.
NOTCH1
,
SMAD6
)
5
–
8
, impeding mechanistic insight and development of therapeutic
strategies. We report the identification of mutations in
ROBO4
,
encoding a factor known to contribute to endothelial performance, that segregate
with disease in two families. Targeted sequencing of
ROBO4
revealed enrichment for rare variants in BAV/AscAA probands compared to
controls. Targeted silencing of
ROBO4
or mutant ROBO4
expression in endothelial cell lines results in impaired barrier function and a
synthetic repertoire suggestive of endothelial-to-mesenchymal transition (EnMT);
concordant BAV/AscAA-associated findings are observed in patients and animal
models deficient for ROBO4. These data identify a novel endothelial etiology for
this common human disease phenotype.
Lipid-laden monocyte/macrophages in atherosclerotic plaques can produce a range of proteinases capable of degrading components of the plaque extracellular matrix, an event that may weaken plaques, rendering them vulnerable to rupture. The effects of differentiation from monocytes to macrophages and exposure to mildly oxidized LDL (Ox-LDL) on the expression of a range of proteinases and their inhibitors were assessed in the human THP-1 cell line. Of 56 proteinases/inhibitors investigated, 17 were upregulated during macrophage differentiation, including several matrix metalloproteinases (MMPs) and cathepsins along with their native inhibitors. Similarly, expression of matrix-degrading proteinases was also increased during differentiation of human primary macrophages. In conjunction, the proteolytic capacity of the cells increased, as assessed by substrate zymography. Subsequent exposure of differentiated THP-1 cells to mildly Ox-LDL increased the expression of a control gene (adipocyte lipid binding protein) and increased the activity of nuclear factor-B and activator protein-1 in serum-free conditions but did not significantly affect the expression of any of the proteinases or inhibitors investigated. These results indicate that in this model macrophage differentiation, rather than exposure to Ox-LDL, has a more important effect on the expression of genes involved in extracellular matrix remodeling. -Whatling, C., H. Björk, S. Gredmark, A. Hamsten, and P. Eriksson. Effect of macrophage differentiation and exposure to mildly oxidized LDL on the proteolytic repertoire of THP-1 monocytes.
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