Lysozyme M–Positive Monocytes Mediate Angiotensin II–Induced Arterial Hypertension and Vascular Dysfunction
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- Philip Wenzel
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Maike Knorr
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Sabine Kossmann
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Jan Stratmann
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Michael Hausding
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Swenja Schuhmacher
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Susanne H. Karbach
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Melanie Schwenk
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Nir Yogev
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Eberhard Schulz
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Matthias Oelze
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Stephan Grabbe
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Helmut Jonuleit
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Christian Becker
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Andreas Daiber
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Ari Waisman
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
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- Thomas Münzel
- From the 2nd Medical Clinic (P.W., M.K., S.K., J.S., M.H., S.S., E.S., M.O., A.D., T.M.), Department of Dermatology (M.S., S.G., H.J., C.B.), Institute for Molecular Medicine (S.H.K., N.Y., A.W.), and Center for Thrombosis and Hemostasis (P.W., M.S., M.H., S.S., T.M.), University Medical Center Mainz, Mainz, Germany.
抄録
<jats:sec> <jats:title>Background—</jats:title> <jats:p>Angiotensin II (ATII), a potent vasoconstrictor, causes hypertension, promotes infiltration of myelomonocytic cells into the vessel wall, and stimulates both vascular and inflammatory cell NADPH oxidases. The predominant source of reactive oxygen species, eg, vascular (endothelial, smooth muscle, adventitial) versus phagocytic NADPH oxidase, and the role of myelomonocytic cells in mediating arterial hypertension have not been defined yet.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> Angiotensin II (1 mg · kg <jats:sup>−1</jats:sup> · d <jats:sup>−1</jats:sup> for 7 days) increased the number of both CD11b <jats:sup>+</jats:sup> Gr-1 <jats:sup>low</jats:sup> F4/80 <jats:sup>+</jats:sup> macrophages and CD11b <jats:sup>+</jats:sup> Gr-1 <jats:sup>high</jats:sup> F4/80 <jats:sup>−</jats:sup> neutrophils in mouse aorta (verified by flow cytometry). Selective ablation of lysozyme M-positive (LysM <jats:sup>+</jats:sup> ) myelomonocytic cells by low-dose diphtheria toxin in mice with inducible expression of the diphtheria toxin receptor (LysM <jats:sup>iDTR</jats:sup> mice) reduced the number of monocytes in the circulation and limited ATII-induced infiltration of these cells into the vascular wall, whereas the number of neutrophils was not reduced. Depletion of LysM <jats:sup>+</jats:sup> cells attenuated ATII-induced blood pressure increase (measured by radiotelemetry) and vascular endothelial and smooth muscle dysfunction (assessed by aortic ring relaxation studies) and reduced vascular superoxide formation (measured by chemiluminescence, cytochrome c assay, and oxidative fluorescence microtopography) and the expression of NADPH oxidase subunits gp91 <jats:sup>phox</jats:sup> and p67 <jats:sup>phox</jats:sup> (assessed by Western blot and mRNA reverse-transcription polymerase chain reaction). Adoptive transfer of wild-type CD11b <jats:sup>+</jats:sup> Gr-1 <jats:sup>+</jats:sup> monocytes into depleted LysM <jats:sup>iDTR</jats:sup> mice reestablished ATII-induced vascular dysfunction, oxidative stress, and arterial hypertension, whereas transfer of CD11b <jats:sup>+</jats:sup> Gr-1 <jats:sup>+</jats:sup> neutrophils or monocytes from gp91 <jats:sup>phox</jats:sup> or ATII receptor type 1 knockout mice did not. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>Infiltrating monocytes with a proinflammatory phenotype and macrophages rather than neutrophils appear to be essential for ATII-induced vascular dysfunction and arterial hypertension.</jats:p> </jats:sec>
収録刊行物
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- Circulation
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Circulation 124 (12), 1370-1381, 2011-09-20
Ovid Technologies (Wolters Kluwer Health)