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

Introduction: Heme oxygenase-1 (HO-1) protects vascular function in hypertension, presumably by anti-inflammatory effect on monocytes. The purpose of this study was to explore the role of HO-1 specifically in monocytes in the development of angiotensin II (AngII) induced hypertension.
Methods and: Lysozyme M (LysM⁺) specific HO-1 knockout mice (LysM^Cre/wtHmox-1^flox/flox) and controls (LysM^Cre/wt) were infused with AngII (1 mg×kg^-1×d^-1 for 7 days using osmotic minipump) or sham-treated. Blood pressure was assessed with tail cuff: Vascular inflammation and reactivity were explored with oxidative fluorescent microtopography and isometric tension studies. Leukocytes 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 strain and aortic reactive oxygen species formation was reduced in AngII-infused LysM^Cre/wtHmox-1^flox/flox mice. AngII-infused LysM^Cre/wtHmox-1^flox/flox presented reduced vascular reactivity impairment with smooth muscle cells-dependent relaxation. Flow cytometry revealed, that vascular accumulation of Ly6G⁺ neutrophils and both Lys6G^-/Ly6C^hi and Ly6G^-/Ly6C^lo monocytes was attenuated in AngII-infused LysM^Cre/wtHmox-1^flox/flox mice compared to controls. 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 LysM^Cre/wtHmox-1^flox/flox mice
Conclusion: In 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 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.