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S. Hazra, Y. P. R. Jarajapu, C. A. Lee, M. E. Boulton, T. S. Kern, J. D. Ash, M. B. Grant; The Common IL6 Signal-Transducing Receptor, gp130, is Implicated in Endothelial Progenitor Cell Dysfunction in Diabetes. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3154.
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gp130 controls the activity of a group of cytokines involved in inflammation and cell survival. Since diabetes is typically associated with increased inflammation and endothelial and endothelial progenitor cell (EPC) dysfunction, we asked whether elimination of gp130 would prevent EPC dysfunction.
Mice carrying the gp130 allele with exon 16 flanked by loxP sites were crossed with transgenic mice that express Cre recombinase under the control of the Tie2 promoter. This genetic combination inactivates gp130 in greater than 95% of vascular endothelial cells and bone marrow derived cells. gp130 knockout (KO) were made diabetic for 6 months and compared to age-matched WT diabetic mice and non-diabetic controls. Peripheral blood and bone marrow were obtained from WT mice with 6 and 12 months of diabetes and age matched controls. Cell number (FACS), cell proliferation (colony formation), iNOS/ eNOS/ nNOS, heme oxygenase-1 (HO-1), PAI-1, MMP-2, and MMP-9 levels (RT-PCR), migration (modified boyden chamber), and NO generation (DAF-FM fluorescence) was determined in EPCs.
As diabetes duration increased, increasing numbers of EPCs were trapped inside the bone marrow (p=0.0003). EPCs from 12 month diabetic mice demonstrated 50% reduction in colony formation compared to age matched control (p=0.0002). eNOS mRNA expression decreased with increasing age in WT mice. iNOS mRNA was increased in diabetic mice but not in WT. HO-1 mRNA increased 3 fold in aged WT mice, but not in diabetics. Diabetic EPCs demonstrated defective migration and reduced bioavailable NO at 6 and 12 months. Diabetic gp130 KO showed greater migratory response and higher NO generation compared to diabetic WT mice (p=0.01).
The common cytokine receptor chain, gp130, plays a central role in loss of EPC functions during diabetes and may offer a potential therapeutic target.
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