Abstract 167: Inhibition of Endoplasmic Reticulum Stress Improves Vascular Function in Type II Diabetic Mice

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Cardiovascular disease is the leading cause of death in the United States with type 2 diabetes (T2D) representing a major risk factor in its development. Vascular dysfunction, characterized by arterial stiffness and endothelial dysfunction occur prior to overt cardiovascular disease and predict future cardiovascular events and mortality in diabetic individuals. Dysfunction of the endoplasmic reticulum (ER), or ER stress, is associated with the development and progression of chronic metabolic diseases such as obesity and T2D. However, the role of ER stress in the development of vascular dysfunction observed in T2D is unclear. We hypothesized that inhibiting ER stress would improve both measures of vascular dysfunction observed in diabetic mice. Male C57BL/6J Leprdb (DB) male mice lacking the leptin receptor were used as a model of T2D. Starting at 4 months of age DB mice were given intraperitoneal injections of ER stress inhibitor, tauroursodeoxycholic acid (TUDCA) at 250mg/kg/day for 4 weeks. C57BL/6J mice were used as controls (n=8 for all groups). Pulse wave velocity (PWV) was measured at baseline (prior to treatment) and after TUDCA treatment. Secondary order mesenteric resistance arteries (MRA) were used to determine endothelial dependent dilation (EDD). DB mice not treated with TUDCA were used for acute studies of EDD by incubating the MRA for 1hr with 0.5mM TUDCA. At baseline, DB mice displayed increased arterial stiffness compared to C57BL/6J controls as measured by PWV (457±25 vs 348±26 cm/s, p<0.05). TUDCA treatment significantly decreased PWV (402±12 cm/s, p<0.05). Both acute and chronic TUDCA treatment improved DB EDD compared to untreated controls (58.4±13.8 and 49.1±6.1%, vs 19.8±9.6%, p<0.05). Expression of ER stress-associated genes CHOP and ATF4 were significantly elevated in DB perivascular adipose tissue and treatment with TUDCA significantly decreased ATF4 compared to DB. In the aorta, TUDCA significantly decreased GRP78 and XBP1 compared to DB. These data support the hypothesis that ER stress contributes to the vascular dysfunction observed in T2D and suggest that ER stress may be a potential target in the treatment of T2D related vascular stiffening and dysfunction.