Objective— Immune cells contribute to angiotensin II (ATII)–induced vascular dysfunction and inflammation. Interferon-γ (IFN-γ), an inflammatory cytokine exclusively produced by immune cells, seems to be involved in ATII-driven cardiovascular injury, but the actions and cellular source of IFN-γ remain incompletely understood. Approach and Results— IFN-γ −/− and Tbx21 −/− mice were partially protected from ATII-induced (1 mg/kg per day of ATII, infused subcutaneously by miniosmotic pumps) vascular endothelial and smooth muscle dysfunction, whereas mice overexpressing IFN-γ showed constitutive vascular dysfunction. Absence of T-box expressed in T cells (T-bet), the IFN-γ transcription factor encoded by Tbx21, reduced vascular superoxide and peroxynitrite formation and attenuated expression of nicotinamide adenosine dinucleotide phosphate oxidase subunits as well as inducible NO synthase, monocyte chemoattractant protein 1, and interleukin-12 in aortas of ATII-infused mice. Compared with controls, IFN-γ −/− and Tbx21 −/− mice were characterized by reduced ATII-mediated vascular recruitment of both natural killer (NK)1.1 + NK-cells as the major producers of IFN-γ and CD11b + Gr-1 low interleukin-12 secreting monocytes. Selective depletion and adoptive transfer experiments identified NK-cells as essential contributors to vascular dysfunction and showed that T-bet + lysozyme M + myelomonocytic cells were required for NK-cell recruitment into vascular tissue and local IFN-γ production. Conclusions— We provide first evidence that NK-cells play an essential role in ATII-induced vascular dysfunction. In addition, we disclose the T-bet-IFN-γ pathway and mutual monocyte–NK-cell activation as potential therapeutic targets in cardiovascular disease.
Background: Inflammatory monocytes are drivers of vascular injury and disease. Results: Depletion of lysozyme M-positive monocytes prevents eNOS uncoupling and iNOS-derived nitro-oxidative stress. Conclusion: Monocytes determine eNOS and iNOS function by directly modulating tetrahydrobiopterin bioavailability. Significance: Understanding the impact of inflammation on endothelial function in detail is essential to identify tailored therapeutic strategies.
SUMMARYIncreased serum levels of interferon-c (IFN-c) have been observed in acute graft-versus-host disease (GVHD). Recent in vitro studies have demonstrated that interleukin-12 (IL-12) and interleukin-18 (IL-18) synergistically up-regulate IFN-c secretion. In this communication, we investigated the factors relevant to IFN-c secretion in acute GVHD. A murine model of acute GVHD was established by injecting donor spleen cells into severe combined immunode®ciency (SCID) mice. A series of specimens, including sera, livers and spleens derived from the GVHD mice, were investigated with histological examination, enzyme-linked immunosorbent assay (ELISA),¯ow cytometry, and semiquantitative reverse transcription±polymerase chain reaction (RT±PCR). IFNc secretion increased in serum 3 days after spleen cell transfer, peaked on day 7, and then gradually decreased close to the baseline level by day 35. A synchronized increase of activated T cells and mRNA expression of IL-12, IL-18 and their respective receptors was observed after spleen cell transfer. However, only the kinetic expression pattern of IL-12 receptor (IL-12R) b2 chains was closely correlated with that of IFN-c, while IL-12 dropped to the baseline level earlier than IFN-c. Therefore, IFN-c expression in the early phase of acute GVHD is a mono-peak and self-restricted pattern. Its secretion is closely related with T-cell activation, the presence of IL-12, IL-18 and their respective receptors. However, the limiting factors for IFN-c secretion seem to be IL-12 and IL-12R b2 chains.
Rationale Immune cells contribute to angiotensin II (ATII) induced vascular dysfunction and inflammation. However, the mechanisms of recruitment and immune effector pathways remain incompletely understood. Objective We tested the hypothesis that interferon-gamma (IFN-γ) and natural killer (NK) cells play a pivotal role in ATII-driven vascular inflammation. Methods and results IFN-γ -/- and Tbx21 -/- mice were partially protected from ATII-induced vascular endothelial and smooth muscle dysfunction, whereas mice overexpressing IFN-γ showed constitutive vascular dysfunction. Absence of T-bet, the IFN-γ transcription factor encoded by Tbx21, reduced vascular superoxide and peroxynitrite formation and attenuated expression of NADPH oxidase subunits as well as inducible NO synthase, monocyte chemoattractant protein 1 and interleukin 12 in aortas of ATII-infused mice. Compared to controls, IFN-γ -/- and Tbx21 -/- mice were characterized by reduced ATII-mediated vascular recruitment of both NK1.1 + NK-cells as the major producers of IFN-γ and CD11b + Gr-1 low IL-12 secreting monocytes. Selective depletion and adoptive transfer experiments identified NK-cells as essential contributors to vascular dysfunction and showed that T-bet + LysM + myelomonocytic cells were required for NK-cell recruitment into vascular tissue and local IFN-γ production. Conclusion We provide first evidence that NK-cells play an essential role in ATII-induced vascular dysfunction. In addition, we disclose the T-bet-IFN-γ pathway and mutual monocyte-NK-cell activation as potential therapeutic targets in cardiovascular disease.
Background Endothelial nitric oxide synthase (eNOS) uncoupling occurs in disease states of vascular dysfunction and amplifies vascular oxidative stress and loss of NO bioactivity. Inflammatory myelomonocytic cells as a major source of superoxide are critical for angiotensin-II induced vascular dysfunction; however their role in mediating eNOS uncopuling has not been defined yet. Methods and results Angiotensin II (1mg/kg/d, 7d) increased the number of CD11b + Gr-1 low iNOS + monocytes and macrophages in mouse aorta (verified by flow cytometry) in paralell to increasing nox4 and heme oxygenase 1 expression (assessed by Western blot analysis) and inducing eNOS uncoupling, measured by differential NOS dependent superoxide formation in the endothelial layer and glutathionylation of eNOS. Toxin mediated ablation of macrophages in LysM iDTR transgenic mice restored all of these parameters. Conversely, ablation of LysM + cells reduced iNOS expression and normalized vascular levels of tetrahydrobiopterin (measured by high-performance liquid chromatography) and expression of the GTP cyclohydrolase-1, essential for tetrahydrobiopterin synthesis, all of which were increased by angiotensin II in control mice. Conclusion Depletion of LysM + monocytes reduces angiotensin II induced eNOS uncopuling in vascular dysfunction, and simultaneously protects from iNOS mediated nitrosative stress: These findings highlight the role of vascular inflammatory cells in disturbed NO-bioactivity and vascular function
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