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S. Li Calzi, M. Tikhonenko, M. Opreanu, S. Hazara, A. D. Bhatwadekar, J. V. Busik, M. B. Grant; Omega-3 Fatty Acid Prevents Diabetic Retinopathy Through Inhibition of Inflammation and Improving EPC Function. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5609.
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Ischemic injury results in endothelial progenitor cell (EPC) recruitment from bone marrow (BM) to areas of vascular injury where they incorporate into damaged vessels and differentiate into endothelial cells to replace diseased endothelium. In diabetics, this response to vascular injury is dramatically decreased. Omega-3 PUFAs (especially DHA) modulate capillary integrity, neovascularization and inflammation in the retina. Retinal levels of Omega-3 PUFAs are decreased in diabetes and increased dietary intake of Omega-3 PUFAs prevents retinopathy. Sphingomyelinases play an important role in cytokine signaling activation in endothelial cells. We recently showed in a type 1 diabetes model that DHA acts through inhibition of ASMase pathway to prevent retinal endothelial cell activation and death.
BBZDR/Wor rats, a model of type 2 diabetes, were fed control diet or diet enriched with DHA. At four months retinas were harvested for assessment of acellular capillaries. EPCs were isolated from blood and bone marrow of non-diabetic, diabetic and DHA-fed diabetic rats and analyzed for cell number and colony formation. Diabetic and normal human EPCs were exposed to DHA, ex vivo, for 18 hours followed by assessment of migration by Boyden chamber assay and measurement of nitric oxide (NO) generation by DAF-FM fluorescence.
Retinas from DHA-fed diabetic rats showed significantly fewer acellular capillaries compared to control diabetic rats. Control diabetic rats showed a dramatic increase in retinal expression of pro-inflammatory and pro-angiogenic mediators (ICAM, IL-6, TNF-alpha) while a DHA-rich diet prevented the increase in ICAM and IL-6 expression and normalized the ASMase protein levels. EPCs from the BM and peripheral blood of diabetic rats had reduced numbers, migration, proliferation and colony formation compared to non-diabetic rats. DHA-fed diabetic rats demonstrated higher numbers of circulating EPCs and improved colony formation. In addition, DHA significantly enhanced human diabetic EPC migration to levels comparable to control cells due to increased NO production.
Our results suggest that DHA supplementation in diabetes improves retinal health not only through direct retinal effects, but also at the level of the bone marrow through the improvement of EPC function and thus retinal vessel repair.
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