Abstract 19953: Interactions of MyD88 and TRIF-Pathways of Innate Immune Responses Regulate Angiotensin II Hypertension
We have reported that angiotensin II (Ang II) induces toll-like receptors (TLRs) in the innate immune system. Here we tested which of the two major adaptor proteins of TLRs, the myeloid differentiation protein 88 (MyD88) or the TIR-domain containing adaptor inducing interferon β (TRIF) mediates the Ang II-induced responses. Infusion of Ang II (3000 ng/kg/min) subcutaneously for 3 weeks in WT mice (C57BL/6J) increased systolic blood pressure to a peak value of 147 ± 4 mm Hg and resulted in a 40% increase in heart weight to body weight ratio (HW/BW). Surprisingly, in MyD88-/- mice the pressor response was enhanced significantly to 163 ± 6 mm Hg (P<0.05) and the HW/BW was increased by 60%. Cardiac and renal RNA expression of TNF-α, NOX4 and Type IA -Ang II receptor were also significantly more elevated in MyD88-/- than in WT. In contrast, in a mouse strain with nonfunctional TRIF gene, Trifmut (C57BL/6J-Ticam1Lps2/J), all the Ang II responses were either uniformly decreased or abrogated. We tested whether the enhanced response in MyD88-/- mice represented a phenomenon of ‘Signaling Flux Redistribution” whereby blockade of one signaling pathway (i.e., MyD88) results in a flux of signaling substrates through the alternative pathway (TRIF). We found that expression of the RNA for chemokine CXCL10 which is dependent on TRIF pathway, was significantly enhanced in MyD88-/- hearts. We also found that expression of transcripts for TLR3, TLR4 and the TRIF adaptor protein were all enhanced in MyD88-/- and must have contributed to the exaggerated Ang II response. Conversely, Trifmut had enhanced MyD88 expression. These results suggest that: (1) Ang II induced hypertension, hypertrophy and inflammatory gene expression are primarily mediated by the TRIF pathway and (2) the MyD88 pathway is simultaneously activated by Ang II and exerts a negative regulatory influence on the pressor and inflammatory responses. We conclude that dual activation of two innate immune pathways defines the net response in WT mice with a significant translational potential. Accordingly, impairment of MyD88 may contribute to pathogenesis of hypertension. Conversely, targeting the TRIF pathway may be therapeutic by blocking the inflammatory response and enhancing the negative regulatory effects of MyD88.
Author Disclosures: M.V. Singh: None. M.Z. Cicha: None. M.W. Chapleau: None. F.M. Abboud: None.
- © 2015 by American Heart Association, Inc.