Angiotensin II-induced Hypertension and Cardiac Hypertrophy are Differentially Mediated by TLR3- and TLR4-Dependent Pathways

Article: Angiotensin II-induced Hypertension and Cardiac Hypertrophy are Differentially Mediated by TLR3- and TLR4-Dependent Pathways

Authors: Madhu V. Singh, Michael Z. Cicha, Sarah Nunez, David K. Meyerholz, Mark W. Chapleau, Francois M. Abboud

Journal: Am J Physiol Heart Circ Physiol. 2019 Feb 22. doi: 10.1152/ajpheart.00697.2018. [Epub ahead of print]

Toll-like receptors (TLR) are key components of the innate immune system that elicit inflammatory responses through the adaptor proteins MyD88 (myeloid differentiation protein 88)- and TRIF (toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β). Previously we demonstrated that TRIF mediates the signaling of angiotensin II (Ang II)- induced hypertension and cardiac hypertrophy. Since TRIF is activated selectively by TLR3 and TLR4, our goals in this study were to determine the roles of TLR3 and TLR4 in mediating Ang II-induced hypertension and cardiac hypertrophy, and associated changes in proinflammatory gene expression in heart and kidney. In wild type (WT) mice, Ang II infusion (1000 ng/kg/min for 3 weeks) increased systolic blood pressure (SBP) and caused cardiac hypertrophy. In Ang II-infused TLR4-deficient mice ( Tlr4del), hypertrophy was significantly attenuated despite a preserved or enhanced hypertensive response. In contrast, in TLR3-deficient mice ( Tlr3-/-), both Ang II-induced hypertension and hypertrophy were abrogated. In WT mice, Ang II increased the expression of several proinflammatory genes in hearts and kidneys that were attenuated in both TLR4- and TLR3-deficient mice compared with WT. We conclude that Ang II activates both TLR4-TRIF and TLR3-TRIF pathways in a non-redundant manner whereby hypertension is totally dependent on activation of the TLR3-TRIF pathway and cardiac hypertrophy is dependent on both TLR3-TRIF and TLR4-TRIF pathways.

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