Abstract 1560: Toll-Like Receptor 4 Upregulates Oxidative Stress by Inhibiting the Upregulation of Extracellular Superoxide Dismutase in Angiotensin II-Induced Hypertension
Objective: Toll-like receptor 4 (TLR4) and angiotensin II (AngII) induce vascular remodeling through the production of reactive oxygen species (ROS) in the vascular wall. On the other hand, it is reported that AngII also increases the level of extracellular superoxide dismutase (ecSOD). However, the relationship between TLR4 and ATII in regulating oxidative stress remains unknown. We investigated the effects of TLR4 on oxidative stress and the expression of ecSOD in AngII-induced hypertension in vivo.
Methods: TLR4−/− and wild-type (WT) mice were randomly subjected to pressure overload by AngII or norepinephrine (NE) for 2 weeks. Blood pressure (BP) was obtained by tail-cuff plethysmography. The total cell number in aortic tunica media, wall-to-lumen (W/L) ratio, and perivascular fibrosis (PVF) of the abdominal aorta were also evaluated. Superoxide (•O2−) content was assessed with fluorescent dihydroethidium staining by a laser scanning confocal microscope. The expression of ecSOD and Cu/ZuSOD in the vascular wall was evaluated with immunoblots.
Results: The control WT and TLR4−/− mice showed a similar level of •O2− content, W/L ratio, PVF, and total cell number as well as the expression of ecSOD and Cu/ZnSOD with no difference in BP. AngII and NE equally and significantly increased systolic BP (SBP) compared with the control mice (p<0.05). In the WT mice, compared with the control WT mice, AngII induced a 10-fold increase in •O2− content in the vascular wall. In addition, 10-fold increase in the expression of ecSOD, 2-fold increase in W/L ratio, and a 1.5-fold increase in PVF were also seen. In contrast, in the TLR4−/− mice, AngII induced a 20-fold increase in the expression of ecSOD compared with the control TLR4−/− mice, while vascular remodeling and the increase in •O2− content in the vasculature were not observed. Total cell number and the expression of Cu/ZnSOD were not affected in both the WT and TLR4−/− mice by AngII-treatment. NE showed little effects on all the indices in the WT and TLR4−/− mice.
Conclusion: These results suggest that TLR4 may play an important role in the upregulation of ROS by inhibiting the expression of ecSOD in Ang II-induced hypertension in vivo.