The life threatening cardiovascular complications of diabetes derive from the formation of fibrofatty atherosclerotic plaques in major blood vessels. Chromatin modifications that sensitise the genome to cardiometabolic risk factors of the diabetic milieu are now widely considered as promising therapeutic targets. However the heterocellular nature of atherosclerosis demands a thorough understanding of cell type-specific chromatin signatures underlying their individual pathologies.
The complex development of atherosclerotic lesions is progressed by three predominant cell types.
The complex development of atherosclerotic lesions is progressed by three predominant cell types.
Vascular endothelial cells intimately engage the circulating
factors of the diabetic milieu, such as hyperglycemia and low-density
lipoprotein. Chronic exposure damages the endothelium, eliciting a state of
endothelial dysfunction characterised by increased vascular permeability and
induction of proinflammatory adhesion and chemotactic molecules that promote
immune cell infiltration.
Macrophage recruitment and accumulation in the subendothelial
space intensifies the inflammatory state by foam cell formation and cytokine
secretion.
As the disease develops, activated vascular smooth muscle
cells migrate from the arterial media to the intima to secrete various
proliferative, fibrotic, osteogenic, and inflammatory factors.
These pathological changes collaborate in the formation of
plaques that in some cases are unstable and prone to rupture, often detaching
and entering the circulation to occlude smaller downstream blood vessels.
Intensified research now implicates lasting gene expression changes in the vasculopathies instigated by the metabolic perturbations of
diabetes.
Despite sharing a common genetic sequence, endothelial, smooth
muscle, and circulating immune cells have distinct epigenomes regulating cell
type–specific gene expression and pathologies.
Further understanding the multitude of epigenomic profiles from
distinct cell populations in the vasculature will reveal new insights in to the development and progression
of atherosclerosis that can be translated to novel therapies in the clinic.
Our review, published in Circulation Research (May 2016), discusses recent key findings in a rapidly burgeoning arena of research into epigenetic mechanisms defining cardiometabolic health and dysfunction. Read the full article here.
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| Distinguishing epigenomic profiles from distinct cell populations in the vasculature. In this example, histone modifications and genomic DNA methylation sequences are derived from human monocyte and endothelial cells using epigenomic profiling methodology combined with computational analyses and integration. Genes associated with differential histone acetylation at the promoter are indicated. Click to enlarge. |
