Abstract 20803: Conditional Knockout of Heme Oxygenase-1 in Lysozyme M Positive Cells Attenuates Angiotensin II-Induced Vascular Inflammation

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Introduction: Heme oxygenase-1 (HO-1) protects vascular function in hypertension, presumably by anti-inflammatory effects on monocytes. The purpose of this study was to explore the role of HO-1 in monocytes in the development of angiotensin II (AngII)-induced hypertension.

Methods: Lysozyme M (LysM+) specific HO-1 knockout mice (LysMCre/wtHmox-1flox/flox) and control mice (LysMCre/wt) were infused with AngII (1 mg·kg-1·d-1 for 7 days using osmotic minipumps) or sham-treated. Blood pressure was assessed with the tail cuff method. Vascular superoxide formation and vascular reactivity were explored with oxidative fluorescent microtopography and isometric tension studies. Vascular inflammation, leukocyte activation and infiltration were assessed with flow cytometry of the aortic tissue and intravital videomicroscopy imaging.

Results: AngII-infusion induced increased systolic blood pressure in both mouse strains. Upon AngII-infusion, LysMCre/wtHmox-1flox/flox mice exhibited reduced aortic reactive oxygen species formation and reduced vascular reactivity impairment with smooth muscle cell-dependent relaxation as compared to AngII-infused control mice. Flow cytometry revealed that vascular accumulation of Ly6G+ neutrophils and both Lys6G-/Ly6Chi and Ly6G-/Ly6Clo monocytes were attenuated in AngII-infused LysMCre/wtHmox-1flox/flox mice as compared to control mice. This was paralleled by reduced aortic mRNA expression of C-C chemokine receptor type 2, reduced ROS formation in circulating blood as well as attenuated leukocyte rolling in carotids of AngII-infused LysMCre/wtHmox-1flox/flox mice compared to control mice.

Conclusion: In a 1-week AngII-infusion model, conditional deletion of HO-1 in LysM+ cells unexpectedly reduced vascular recruitment and protected from ROS formation in blood and from infiltration of inflammatory cells, but not from arterial hypertension. Further investigations are needed to test the impact of myelomonocyte-specific deficiency of HO-1 on the phenotype and transcriptome of monocytes since very recent studies suggest a specific role of HO-1 in the maturation and trafficking of these cells.

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