Abstract 181: Toll-Like Receptor 9 Activation Leads to Augmented Thromboxane A2 Induced Contractions in Rat Aorta
Evidence has supported the involvement of the immune system in the development of vascular diseases. Toll-like receptor 9 (TLR 9) is a pattern recognition receptor of the immune system which is activated by exogenous DNA (bacterial and viral) and endogenous mitochondrial DNA (mtDNA) containing unmethylated CpG motifs. Activation of TLR 9 in immune cells leads to the release of pro-inflammatory cytokines via nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. TLR 9 is also expressed in the vasculature; however, its role in vascular diseases remains to be elucidated. Therefore, we hypothesized that TLR 9 activation, using a synthetic oligonucleotide containing unmethylated CpG motifs [ODN 2395 (ODN); 10-5 M], would augment aortic contractility in female, 16 weeks old, Sprague Dawley rats. Contractile concentration response curves were performed ex vivo using the myograph to thromboxane A2 (TxA2) mimetic (U-46619; 10-9-3x10-6 M) and phenylephrine (PE; 10-9-3x10-5 M), following incubation for 15 hours with ODN or vehicle (Veh). Results revealed that ODN amplified the contractile responses to U-46619 [Emax (% max KCl), ODN: 262±18 vs. Veh: 178±13; Fig. A]. Moreover, ODN attenuated aortic sensitivity to PE compared to Veh [pD2, ODN: 6.4±0.1 vs. Veh: 6.8±0.2; Fig. B]. These data suggest that TLR 9 activation heightened aortic contractility to U-46619. We propose that mtDNA activation of TLR 9, released during necrotic events of vascular remodeling, has pro-inflammatory effects that contribute to increased TxA2 receptor-associated contractions. This could potentially lead to vascular dysfunction and vascular diseases such as hypertension.
- © 2012 by American Heart Association, Inc.