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Isha Sharma, Nasser Rizk, Amina Sadeh Falel, Mohamed Al-Sayed Al-Shabrawey; Docosahexaenoic acid (DHA)-a novel therapeutic intervention for mitigating hypoxia induced retinal endothelial dysfunction. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):21. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Hypoxia plays a key role in pathological retinal neovascularization in diabetic retinopathy (DR). Therapeutic interventions to halt the disease progression is limited due to several side effects and thus effective and alternative strategies are to be explored. In the present study, we investigated the effect of exogenous supplementation of docosahexaenoic acid (DHA, 30 µM) to human endothelial microvascular cells (HRECs) under hypoxia (1% oxygen, 48 h).
HRECs were analyzed for cell barrier function and proliferation by measuring changes in transcellular electrical resistance (TER). Apoptosis, oxidative stress and cell cycle analysis were carried out. Real-time PCR and protein expression analysis was performed for various key inflammatory and angiogenic markers.
Hypoxia resulted in the reduced TER, it was significantly enhanced in cells treated with DHA+hypoxia revealing DHA led restoration of cell-barrier function in hypoxic HRECs. An automated TER based wound-healing assay performed in HRECs demonstrated that proliferation and migration induced by hypoxia was significantly reduced under DHA supplementation.These results were further supported by the reduced tube formation in hypoxia+DHA treated HRECs as compared to hypoxic HRECs. Furthermore, there was a 3-fold and 5-fold increase in the level of apoptosis and oxidative stress respectively in hypoxic HRECs while DHA supplementation significantly reduced the titers of apoptosis and oxidative stress. Cell cycle analysis revealed that hypoxia induced cell growth retardation was due to G1-arrest while DHA treatment resulted in elevated number of cells in G1-phase of cell cycle. These effects were linked to the hypoxia induced modulation of various regulatory transcription factors and genes like HIF-1alpha, pparg , vegf a and c and pedf. These results corroborated with the levels of protein abundance for various angiogenic as well as pro-inflammatory markers.
Overall, the study shows the potent effect of DHA in preserving microvascular functions of HRECs under hypoxia and identifies several key factors mediating anti-inflammatory, -angiogenic and -oxidative effects of DHA supplement. The study thus proposes that DHA as a dietary supplement have the potential to be utilized as a readily available, safe and inexpensive drug against microvascular complications of DR.
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