Abstract 072: TRIF-Pathway of Innate Immune Responses Mediates Angiotensin II Hypertension
We tested the role of two distinct adaptors of toll-like receptor (TLR) signaling on Ang II-induced hypertension and cardiac hypertrophy. These TLR adaptors, myeloid differentiation protein 88 (MyD88) and TIR domain-containing adaptor inducing interferon β (TRIF) facilitate distinct inflammatory signaling pathways. In an earlier study, we reported that MyD88-/- mice are protected from cardiac hypertrophy and pro-inflammatory gene expression after myocardial infarction. Our current results with 3 weeks infusion of Ang II (3000 ng/kg/min) vs. saline indicate that in MyD88-/- mice, the pressor response to Ang II and cardiac hypertrophy were increased more than in wild type (WT) mice. In Ang II-infused WT, systolic blood pressure (SBP) peaked at 147 ± 4 mmHg whereas in Ang II-infused MyD88-/- mice SBP reached a peak value of 163 ± 6 mmHg. However, in mice with non-functional TRIF adaptor mutant (Trifmut), SBP did not increase during Ang II infusion and remained similar to the SBP in saline-infused mice (115 ± 3 mmHg). Baseline SBP was not different among WT, MyD88-/- and Trifmut mice. The increase in heart weight to body weight ratio (HW/BW) between saline and Ang II-infused mice was greater in MyD88-/- mice than WT mice (60% increase in MyD88-/- vs. 40% increase in WT), whereas it was less in Trifmut mice (22% increase). Accordingly, expression of several inflammatory genes (Tnfa, Nox4 and Agtr1a) was significantly greater (P< 0.05) in the heart and kidney of Ang II-infused MyD88-/- mice compared with Ang II-infused WT mice, whereas expression of these genes in Trifmut mice was either unchanged or reduced. We conclude that- (1) Ang II-induced hypertension, cardiac hypertrophy and inflammatory gene expression are mediated by activation of a TRIF-dependent pathway, but not by the MyD88-dependent pathways, and (2) Enhanced Ang II effects on SBP and hypertrophy in MyD88-/- mice suggest that MyD88 may serve as a negative regulator of the TRIF pathway in Ang II-induced hypertension. Selective targeting of these adaptor proteins may have significant therapeutic implications.
Author Disclosures: M.V. Singh: None. M.Z. Cicha: None. M.W. Chapleau: None. F.M. Abboud: None.
- © 2015 by American Heart Association, Inc.