Abstract 10579: Endothelial Specific Redox Signalling Regulates Susceptibility to Aortic Dissection Through Endothelial Cyclophilin A secretion
Aortic dissection is a severe and often fatal condition, and has been shown to be associated with vascular oxidative stress. One of the main sources of oxidative stress in the vasculature is NADPH oxidase (Nox) found in both vascular smooth muscle cells (VSMCs) and endothelial cells. Recent evidence suggests an important role for VSMC Nox in the development of aortic dissection however, the role of endothelial Nox remains unclear. To address this question, we used mice with specific endothelial-targeted over-expression of Nox 2 (Nox2-Tg). Nox2-Tg mice had greater endothelial reactive oxygen species (ROS) production at both baseline and in response to AngII stimulation compared to WT littermates. Male mice at 6 months of age were treated with AngII (1mg/kg/day) delivered through subcutaneous mini-pump for 28 days. There was no significant difference in the pressor responses between Nox2-Tg and WT littermates (Nox2-Tg: 122±6mmHg vs. WT: 121±7mmHg, n=11). However, 5/11 Nox2-Tg mice developed aortic dissections compared to 0/11 WT mice (P<0.001). Immunohistochemistry revealed significantly increased endothelial VCAM-1, MMP activity and CD45+ inflammatory cell recruitment in aortas of Nox2-Tg mice compared with WT and saline controls 5 days after Ang II treatment (P<0.05). Inflammatory cell recruitment was further confirmed by FACS analysis of cells isolated from explanted aortas. In addition, explanted aortas from the Nox2-Tg had significantly increased Cyclophilin A (Cypa) secretion at both baseline and after 5 days of AngII treatment compared to WT. Primary endothelial cells from Nox2-Tg had increased basal secretion of Cypa and Erk1/2 activity compared to endothelial cells from WT. However, no difference in secreted Cypa or Erk1/2 activity was observed in VSMC from Nox2-Tg vs. WT either basally or after AngII stimulation. In conclusion, these results demonstrate for the first time that changes in endothelial redox state through the specific over-expression of endothelial Nox2 is sufficient to induce aortic dissection in response to AngII. Endothelial secreted Cypa could be the signalling mechanism by which increased endothelial ROS leads to increased susceptibility to aortic dissection.
- © 2011 by American Heart Association, Inc.