Dual Activation of TRIF and MyD88 Adaptor Proteins by Angiotensin II Evokes Opposing Effects on Pressure, Cardiac Hypertrophy, and Inflammatory Gene Expression

Madhu V Singh; Michael Z Cicha; David K Meyerholz; Mark W Chapleau; François M Abboud

doi:10.1161/HYPERTENSIONAHA.115.06011

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Dual Activation of TRIF and MyD88 Adaptor Proteins by Angiotensin II Evokes Opposing Effects on Pressure, Cardiac Hypertrophy, and Inflammatory Gene Expression

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Dual Activation of TRIF and MyD88 Adaptor Proteins by Angiotensin II Evokes Opposing Effects on Pressure, Cardiac Hypertrophy, and Inflammatory Gene Expression

Madhu V Singh, Michael Z Cicha, David K Meyerholz, Mark W Chapleau and François M Abboud

Hypertension (Dallas, Tex. 1979), Vol.66(3), pp.647-656

09/2015

DOI: 10.1161/HYPERTENSIONAHA.115.06011

PMCID: PMC4537368

PMID: 26195481

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Abstract

Hypertension is recognized as an immune disorder whereby immune cells play a defining role in the genesis and progression of the disease. The innate immune system and its component toll-like receptors are key determinants of the immunologic outcome through their proinflammatory response. Toll-like receptor-activated signaling pathways use several adaptor proteins of which adaptor proteins myeloid differentiation protein 88 (MyD88) and toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF) define 2 major inflammatory pathways. In this study, we compared the contributions of MyD88 and TRIF adaptor proteins to angiotensin II (Ang II)-induced hypertension and cardiac hypertrophy in mice. Deletion of MyD88 did not prevent cardiac hypertrophy and the pressor response to Ang II tended to increase. Moreover, the increase in inflammatory gene expression (Tnfa, Nox4, and Agtr1a) was significantly greater in the heart and kidney of MyD88-deficient mice when compared with wild-type mice. Thus, pathways involving MyD88 may actually restrain the inflammatory responses. However, in mice with nonfunctional TRIF (Trif(mut) mice), Ang II-induced hypertension and cardiac hypertrophy were abrogated, and proinflammatory gene expression in heart and kidneys was unchanged or decreased. Our results indicate that Ang II induces activation of a proinflammatory innate immune response, causing hypertension and cardiac hypertrophy. These effects require functional adaptor protein TRIF-mediated pathways. However, the common MyD88-dependent signaling pathway, which is also activated simultaneously by Ang II, paradoxically exerts a negative regulatory influence on these responses.

Angiotensin II - pharmacology

Gene Expression - drug effects

Adaptor Proteins, Vesicular Transport - genetics

Myeloid Differentiation Factor 88 - genetics

Adaptor Proteins, Vesicular Transport - metabolism

Mice, Knockout

Inflammation - metabolism

Animals

Inflammation - genetics

Blood Pressure - drug effects

Blood Pressure - physiology

Mice

Cardiomegaly - genetics

Myeloid Differentiation Factor 88 - metabolism

Cardiomegaly - metabolism

Details

Title: Subtitle: Dual Activation of TRIF and MyD88 Adaptor Proteins by Angiotensin II Evokes Opposing Effects on Pressure, Cardiac Hypertrophy, and Inflammatory Gene Expression
Creators: Madhu V Singh - From the Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine (M.V.S., M.W.C., F.M.A.), Department of Molecular Physiology and Biophysics, Carver College of Medicine (M.W.C., F.M.A.), and Department of Pathology (D.K.M.), University of Iowa, Iowa City; and Department of Veterans Affairs Medical Center, Iowa City, IA (M.Z.C., M.W.C.). madhu-singh@uiowa.edu francois-abboud@uiowa.edu
Michael Z Cicha - From the Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine (M.V.S., M.W.C., F.M.A.), Department of Molecular Physiology and Biophysics, Carver College of Medicine (M.W.C., F.M.A.), and Department of Pathology (D.K.M.), University of Iowa, Iowa City; and Department of Veterans Affairs Medical Center, Iowa City, IA (M.Z.C., M.W.C.)
David K Meyerholz - From the Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine (M.V.S., M.W.C., F.M.A.), Department of Molecular Physiology and Biophysics, Carver College of Medicine (M.W.C., F.M.A.), and Department of Pathology (D.K.M.), University of Iowa, Iowa City; and Department of Veterans Affairs Medical Center, Iowa City, IA (M.Z.C., M.W.C.)
Mark W Chapleau - From the Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine (M.V.S., M.W.C., F.M.A.), Department of Molecular Physiology and Biophysics, Carver College of Medicine (M.W.C., F.M.A.), and Department of Pathology (D.K.M.), University of Iowa, Iowa City; and Department of Veterans Affairs Medical Center, Iowa City, IA (M.Z.C., M.W.C.)
François M Abboud - From the Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine (M.V.S., M.W.C., F.M.A.), Department of Molecular Physiology and Biophysics, Carver College of Medicine (M.W.C., F.M.A.), and Department of Pathology (D.K.M.), University of Iowa, Iowa City; and Department of Veterans Affairs Medical Center, Iowa City, IA (M.Z.C., M.W.C.). madhu-singh@uiowa.edu francois-abboud@uiowa.edu
Resource Type: Journal article
Publication Details: Hypertension (Dallas, Tex. 1979), Vol.66(3), pp.647-656
DOI: 10.1161/HYPERTENSIONAHA.115.06011
PMID: 26195481
PMCID: PMC4537368
NLM abbreviation: Hypertension
ISSN: 0194-911X
eISSN: 1524-4563
Publisher: United States
Grant note: P01 HL014388 / NHLBI NIH HHS I01 BX001414 / BLRD VA HL 14388 / NHLBI NIH HHS
Language: English
Date published: 09/2015
Academic Unit: Molecular Physiology and Biophysics; Pathology; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984025352602771

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