Angiotensin II-induced hypertension and cardiac hypertrophy are differentially mediated by TLR3- and TLR4-dependent pathways

Abstract

Toll-like receptors (TLR) are key components of the innate immune system that elicit inflammatory responses through the adaptor proteins myeloid differentiation protein 88 (MyD88) and Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF). 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 (1,000 ng·kg−1·min−1 for 3 wk) increased systolic blood pressure 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 nonredundant manner whereby hypertension is dependent on activation of the TLR3-TRIF pathway and cardiac hypertrophy is dependent on both TLR3-TRIF and TLR4-TRIF pathways. NEW & NOTEWORTHY Angiotensin II (ANG II)-induced hypertension is dependent on the endosomal Toll-like receptor 3 (TLR3)-Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF) pathway of the innate immune system but not on cell membrane localized TLR4. However, ANG II-induced cardiac hypertrophy is regulated by both TLR4-TRIF and TLR3-TRIF pathways. Thus, ANG II-induced rise in systolic blood pressure is independent of TLR4-TRIF effect on cardiac hypertrophy. The TLR3-TRIF pathway may be a potential target of therapeutic intervention.

Exercise Training Attenuates Hypertension Through TLR4/MyD88/NF-κB Signaling in the Hypothalamic Paraventricular Nucleus

“…Recently studies have shown that TLR4 is an important receptor for the signaling transduction in the innate immune system, which affects various cardiovascular diseases such as heart failure and hypertension (Kandadi et al, 2012; Wang S.Y. et al, 2018; Dai et al, 2019; Singh et al, 2019). TLR4 has been recognized as an important regulator for NF-κB (Li et al, 2016).…”

Key Player in Cardiac Hypertrophy, Emphasizing the Role of Toll-Like Receptor 4

“…It was reported that the TRIF-dependent pathway is shown to be a determinant in hypertension and cardiac hypertrophy, whereas the MyD88-dependent pathway is not responsible (97). Indeed, in settings of Ang II infusions at high rates (3,000 ng/kg/min), cardiac hypertrophy was found to have been reduced in TRIF deficient mice but aggravated in MyD88 knockout mice compared to wild type mice by measuring the ratio of heart weight to body weight, with a similar trend also observed in systolic blood pressure (97,98). Furthermore, the inflammatory response not only did not decrease but increased in MyD88 deficient mice, accompanied by the increase in cardiac expression of TLR4 and TRIF, indicating that MyD88dependent signaling functions as a negative regulator of proinflammatory pathological response mediated by TRIF in the context of high dose Ang II-induced cardiac hypertrophy (97), and infusion doses of Ang II may cause MyD88-dependent signaling functions in cardiac hypertrophy differing from the usual response.…”

“…Furthermore, the inflammatory response not only did not decrease but increased in MyD88 deficient mice, accompanied by the increase in cardiac expression of TLR4 and TRIF, indicating that MyD88dependent signaling functions as a negative regulator of proinflammatory pathological response mediated by TRIF in the context of high dose Ang II-induced cardiac hypertrophy (97), and infusion doses of Ang II may cause MyD88-dependent signaling functions in cardiac hypertrophy differing from the usual response. On this basis, further studies demonstrated that activation of TRIF signaling releases type I IFNs that are responsible for Ang II-induced hypertension and cardiac hypertrophy, whereas the TLR3-mediated TRIF signaling not only induces hypertension but also cardiac hypertrophy in response to Ang II infusion, but the TLR4/TRIF pathway is only required for cardiac hypertrophy (98). However, it is not clear whether there are similar phenomena in pressure overloador obesity-induced cardiac hypertrophy model.…”

Impact of Gut Microbiota Composition on Onset and Progression of Chronic Non-Communicable Diseases

“…The latter is a factor of the innate immune system involved in system inflammation; in recent years, its putative role in the pathogenesis of HTN has emerged. Animal studies have shown how angiotensin II acts through the activation of TLR4 pathways; however, the precise mechanism has yet to be elucidated [111,147]. This study shows that probiotics represent a possible therapeutic tool for the treatment of genetic HTN.…”