Chronic inhibition of chemokine receptor CXCR2 attenuates cardiac remodeling and dysfunction in spontaneously hypertensive rats

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2019-12, Vol.1865 (12), p.165551-165551, Article 165551
• Main Authors: Zhang, Yun-Long, Geng, Chi, Yang, Jie, Fang, Jiao, Yan, Xiao, Li, Pang-Bo, Zou, Lei-Xin, Chen, Chen, Guo, Shu-Bin, Li, Hui-Hua, Liu, Ying
• Format: Article
• Language: English
• Subjects: Animals; Blood Pressure - drug effects; Cardiac remodeling; Cardiomegaly - drug therapy; Cardiomegaly - etiology; Cardiomegaly - physiopathology; Chemokine receptor CXCR2; Heart - drug effects; Heart - physiopathology; Hypertension - complications; Hypertension - drug therapy; Hypertension - physiopathology; Inflammation; Macrophage infiltration; Oxidative stress; Phenylurea Compounds - therapeutic use; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Interleukin-8B - antagonists & inhibitors; Spontaneously hypertensive rats; Ventricular Remodeling - drug effects
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2019.165551

System hypertension is a major risk factor for cardiac hypertrophy and heart failure. Our recent findings reveal that the ablation or inhibition of C-X-C chemokine receptor (CXCR) 2 blocks this process in mice; however, it is not clear whether the pharmacological inhibition of CXCR2 attenuates hypertension and subsequent cardiac remodeling in spontaneously hypertensive rats (SHRs). In the present study, we showed that chemokines (CXCL1 and CXCL2) and CXCR2 were significantly upregulated in SHR hearts compared with Wistar–Kyoto rat (WKY) hearts. Moreover, the administration of CXCR2-specific inhibitor N-(2-hydroxy-4-nitrophenyl)-N′-(2-bromophenyl)-urea (SB225002) in SHRs (at 2 months of age) for an additional 4 months significantly suppressed the elevation of blood pressure, cardiac myocyte hypertrophy, fibrosis, inflammation, and superoxide production and improved heart dysfunction in SHRs compared with vehicle-treated SHRs. SB225002 treatment also reduced established hypertension, cardiac remodeling and contractile dysfunction. Moreover, CXCR2-mediated increases in the recruitment of Mac-2-positive macrophages, proinflammatory cytokines, vascular permeability and ROS production in SHR hearts were markedly attenuated by SB225002. Accordingly, the inhibition of CXCR2 by SB225002 deactivates multiple signaling pathways (AKT/mTOR, ERK1/2, STAT3, calcineurin A, TGF-β/Smad2/3, NF-κB-p65, and NOX). Our results provide new evidence that the chronic blocking of CXCR2 activation attenuates progression of cardiac hypertrophic remodeling and dysfunction in SHRs. These findings may be of value in understanding the benefits of CXCR2 inhibition for hypertensive cardiac hypertrophy and provide further support for the clinical application of CXCR2 inhibitors for the prevention and treatment of heart failure. •Blocking of CXCR2 activation attenuates hypertension and cardiac remodeling in spontaneously hypertensive rats.•Administration of a CXCR2 inhibitor SB225002 significantly inhibits inflammation and oxidative stress.•Inhibition of CXCR2 reduces activation of AKT/mTOR, TGF-β/Smad2/3, and NF-kB signaling pathways.