Genetic and Pharmacologic Inhibition of the Chemokine Receptor CXCR2 Prevents Experimental Hypertension and Vascular Dysfunction
Background—The recruitment of leukocytes to the vascular wall is a key step in hypertension development. Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases, however, the role of CXCR2 in hypertension development and the underlying mechanisms remain unknown.
Methods—Angiotensin II (490 ng·kg-1·min-1) or DOCA-salt-induced mouse hypertensive models in genetic ablation, pharmacological inhibition of CXCR2 and adoptive bone marrow transfer mice were used to determine the role of CXCR2 in hypertension (measured by radiotelemetry and tail-cuff system), inflammation (verified by flow cytometry and quantitative real-time PCR analysis), vascular remodeling (studied by haematoxylin and eosin (H&E) and Masson's trichrome staining), vascular dysfunction (assessed by aortic ring), and oxidative stress (indicated by NADPH oxidase activity, DHE staining and quantitative real-time PCR analysis). Moreover, the blood CXCR2+ cells in normotensive controls and hypertension patients were analyzed by flow cytometry.
Results—Angiotensin II significantly up-regulated the expression of CXCR2 mRNA and protein, and increased the number of CD45+ CXCR2+ cells in mouse aorta (n=8 per group). Selective CXCR2 knockout (CXCR2-/-) or pharmacological inhibition of CXCR2 markedly reduced angiotensin II- or DOCA-salt-induced blood pressure elevation, aortic thickness and collagen deposition, accumulation of pro-inflammatory cells into the vascular wall, and the expression of cytokines (n=8 per group). CXCR2 inhibition also ameliorated angiotensin II-induced vascular dysfunction and reduced vascular superoxide formation, NADPH activity and the expression of NADPH oxidase subunits (n=6 per group). Bone marrow reconstitution of wild-type (WT) mice with CXCR2-/- bone marrow cells also significantly abolished angiotensin II-induced responses (n=6 per group). Importantly, CXCR2 blockade reversed established hypertension induced by angiotensin II or DOCA-salt challenge (n=10 per group). Furthermore, we demonstrated that CXCR2+ pro-inflammatory cells were higher in hypertensive patients (n=30) compared with normotensive individuals (n=20).
Conclusions—Infiltration of CXCR2+ cells plays a pathogenic role in arterial hypertension and vascular dysfunction. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat hypertension.
- Received December 5, 2015.
- Revision received June 10, 2016.
- Accepted July 8, 2016.
Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.