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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Zhang, Yun-Long¹  Geng, Chi²  Yang, Jie²  Fang, Jiao²  Yan, Xiao²  Li, Pang-Bo¹  Zou, Lei-Xin²  Chen, Chen²  Guo, Shu-Bin¹  Li, Hui-Hua¹  Liu, Ying² 

[1] Capital Med Univ, Beijing Chaoyang Hosp, Beijing Key Lab Cardiopulm Cerebral Resuscitat, Dept Emergency Med, Beijing 100020, Peoples R China

[2] Dalian Med Univ, Affiliated Hosp 1, Inst Cardiovasc Dis, Dept Cardiol, Dalian 116011, Peoples R China

关键词: Chemokine receptor CXCR2;    Spontaneously hypertensive rats;    Cardiac remodeling;    Inflammation;    Oxidative stress;    Macrophage infiltration;   

DOI  :  10.1016/j.bbadis.2019.165551

来源: Elsevier

【 摘 要 】

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-beta/Smad2/3, NF-kappa B-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

【 授权许可】

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