title: Dual Activation of TRIF and MyD88 Adaptor Proteins by Angiotensin II Evokes Opposing Effects on Pressure, Cardiac Hypertrophy, and Inflammatory Gene Expression.
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.
authors.affiliation: 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.
authors.forename: Madhu V
authors.initials: MV
authors.lastname: Singh
authors.affiliation: 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.).
authors.forename: Michael Z
authors.initials: MZ
authors.lastname: Cicha
authors.affiliation: 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.).
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.affiliation: 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.).
authors.forename: Mark W
authors.initials: MW
authors.lastname: Chapleau
authors.affiliation: 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.
authors.forename: François M
authors.initials: FM
authors.lastname: Abboud
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000804:Angiotensin II; D053594:Myeloid Differentiation Factor 88; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse
keywords: MyD88 protein; TICAM-1 protein; angiotensin II; gene expression; hypertension; toll-like receptors