| Authors |
Hazra S, Rasheed A, Bhatwadekar A, Wang X, Shaw LC, Patel M, Caballero S,
Magomedova L, Solis N, Yan Y, Wang W, Thinschmidt JS, Verma A, Li Q, Levi M,
Cummins CL, Grant MB
|
| Submitted By |
Moshe Levi on 1/30/2013 |
| Status |
Published |
| Journal |
Diabetes |
| Year |
2012 |
| Date Published |
12/1/2012 |
| Volume : Pages |
61 : 3270 - 3279 |
| PubMed Reference |
|
| Abstract |
Endothelial progenitor cells (EPCs), critical for mediating vascular repair, are
dysfunctional in a hyperglycemic and/or hypercholesterolemic environment. Their
dysfunction contributes to the progression of diabetic macro- and microvascular
complications. Activation of "cholesterol-sensing" nuclear receptors, the liver
X receptors (LXRa/LXR脽), protects against atherosclerosis by transcriptional
regulation of genes important in promoting cholesterol efflux and inhibiting
inflammation. We hypothesized that LXR activation with a synthetic ligand would
correct diabetes-induced EPC dysfunction and improve diabetic retinopathy.
Studies were performed in streptozotocin (STZ)-injected DBA/2J mice fed a
high-fat Western diet (DBA/STZ/WD) and treated with the LXR agonist GW3965 and
in LXRa(-/-), LXR脽(-/-), and LXRa/脽(-/-) mice. Retinas were evaluated for number
of acellular capillaries and glial fibrillary acidic protein (GFAP)
immunoreactivity. Bone marrow EPCs were analyzed for migratory function and gene
expression. Compared with vehicle-treated DBA/STZ/WD mice, GW3965 treated mice
showed fewer acellular capillaries and reduced GFAP expression. These mice also
exhibited enhanced EPC migration and restoration of inflammatory and oxidative
stress genes toward nondiabetic levels. LXRa(-/-), LXR脽(-/-), and LXRa/脽(-/-)
mice developed acellular capillaries and EPC dysfunction similar to the
DBA/STZ/WD mice. These studies support a key role for LXR in retinal and bone
marrow progenitor dysfunction associated with type 1 diabetes. LXR agonists may
represent promising pharmacologic targets for correcting retinopathy and EPC
dysfunction.
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