Abstract 16211: Activation of Endothelial Toll Like Receptor 3 Impairs Endothelial Function and Promotes Atherosclerosis
Rationale: Atherosclerosis is chronic inflammatory diseases characterized by activation of the innate and acquired immune system. Specialized protein receptors of the innate immune system recognize products of microorganisms and endogenous ligands such as nucleic acids. Toll like receptor 3 (TLR3) for example detects long double-stranded RNA and is abundantly expressed in endothelial cells.
Objective: We sought to determine the effects of TLR3 in endothelial biology and atherogenesis.
Methods and Results: Intravenous injection of polyIC, a synthetic dsRNA-analogon and TLR3 ligand, impaired endothelium-dependent vasodilation, increased vascular production of reactive oxygen species (ROS) and reduced re-endothelialisation after carotid artery injury in wild-type mice compared to controls, but had no effect in TLR3-/- animals. TLR3 stimulation not only induced endothelial dysfunction but also enhanced the formation of atherosclerotic plaques in ApoE-/- mice. In vitro incubation of endothelial cells with polyIC induced the production of the proinflammatory cytokines IL-8 and IP-10, increased ROS formation, diminished proliferation and elevated apoptosis, suggesting that endothelial cells are able to directly detect and respond to TLR3 ligands. Neutralizing IL-8 and IP-10 antagonizes the observed negative effects of polyIC. Surprisingly, we found elevated levels of circulating EPC in polyIC treated mice although they displayed endothelial dysfunction. Stimulation of TLR3 in cultured EPC however, led to raised ROS formation, increased apoptosis and reduced migration. Injection of EPC that had been incubated with polyIC ex vivo hindered the re-endothelialisation after carotid artery injury. Therefore, also EPC function is affected by TLR3 stimulation. Finally, ApoE-/- TLR3-/- mice exhibited improved endothelial function and reduced atherosclerotic plaques compared to ApoE-/- TLR3+/+ littermates. Thus, TLR3 signaling is involved in atherogenesis in ApoE-/- without external stimulation.
Conclusion: Immunorecognition of long double-stranded RNA by endothelial cells may be an important mechanism involved in endothelial cell activation, the development of endothelial dysfunction and ultimately atherosclerosis.
- © 2011 by American Heart Association, Inc.