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Islam Mohamed, Modesto Rojas, Ruth Caldwell, Adviye Ergul, Azza El-Remessy; Role of TXNIP in High fat Diet-induced Inflammasome Activation in Retinal Endothelial Cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2701.
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© ARVO (1962-2015); The Authors (2016-present)
Obesity is the fastest growing risk factor for vascular diseases. Thioredoxin interacting protein (TXNIP) was recognized as an activator of NOD-like receptor protein (NLRP3)-inflammasome. Nevertheless, there is a gap in knowledge whether obesity-induced TXNIP expression results in inflammasome activation in endothelial cells.
8-13 week old male Wistar control rats were compared to rats fed with high fat diet (HFD, 45-60% fat) for 8-10 weeks. 6 weeks old, age and gender matched C57Bl/6J wild type (WT) mice fed with normal rat chow were compared to TXNIP dificient (TKO) mice fed with high fat diet (HFD, 60% fat) for 7-8 weeks. Human retinal endothelial cells (HRECs) were incubated with increasing concentrations of sodium palmitate coupled to bovine serum albumin (Pal-BSA) for 8-14 hours alone or in combination with 100µM peroxynitrite (PN).
In Wistar rats, HFD significantly increased retinal TXNIP mRNA and protein expression and its association with NLRP3. This coincided with increased oxidative/nitrative stress, cleaved interleukin 1-beta (IL-1β) expression and acellular capillary formation, the hallmark of retinal ischemia. Colocalization studies identified retinal vasculature as prominent tissue for enhanced TXNIP expression. TKO mice showed reduced numbers of adherent leucocytes to retinal vessels compared to WT mice in response to HFD. In vitro, 400µM Pal-BSA triggered maximum expression of TXNIP, cleaved caspase-1 and IL-1β in HRECs. Combining 100µM PN with 400µM Pal-BSA exacerbated these effects with parallel increases in adhesion molecules (ICAM-1 & PECAM-1) and the proapoptotic cleaved caspase-3 expression. Knocking down TXNIP expression appears to abolish such response in HRECs.
These studies highlight a novel role for TXNIP in obesity-induced oxidative/inflammatory response in retinal vasculature via NLRP3-inflammasome activation. Delineating this mechanism will help identifying innovative therapeutic targets for early intervention in obesity and prediabetes-related vascular complications affecting ~79 Million Americans.
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