Abstract
The expression level of CC-chemokine receptor 5 (CCR5) is enhanced post inflammatory stimulations and might play a crucial role on inflammatory cells infiltration post myocardial ischemia. The purpose of this study was to evaluate the role of CCR5 on myocardial ischemia–reperfusion (I/R) injury in rats. Adult male rats were randomized to sham group, I/R group (I/R, 30 min coronary artery occlusion followed by 2-h reperfusion), ischemic preconditioning (I/R + Pre), CCR5 antibody group [I/R + CCR5Ab (0.2 mg/kg)], and CCR5 agonist group [I/R + CCR5Ago, RNATES (0.1 mg/kg)], n = 12 each group. The serum level of creatine kinase (CK) and tumor necrosis factor α (TNF-α) were measured by ELISA. Myocardial infarction size and myeloperoxidase (MPO) activity were determined. Myocardial protein expression of CCR5 and intercellular adhesion molecule-1 (ICAM-1) were evaluated by Western blotting and immunohistochemistry staining, respectively. Myocardial nuclear factor-kappa B (NF-κB) activity was assayed by electrophoretic mobility shift assay. Myocardial CCR5 protein expression was significantly reduced in I/R + Pre group (P < 0.05 vs. I/R) and further reduced in I/R + CCR5Ab group (P < 0.05 vs. I/R + Pre). LVSP and ±dP/dt max were significantly lower while serum CK and TNF-α as well as myocardial MPO activity, ICAM-1 expression, and NF-κB activity were significantly higher in I/R group than in sham group (all P < 0.05), which were significantly reversed by I/R + Pre (all P < 0.05 vs. I/R) and I/R + CCR5Ab (all P < 0.05 vs. I/R + Pre) while aggravated by I/R + CCR5Ago (all P < 0.05 vs. I/R). Our results suggest that blocking CCR5 attenuates while enhancing CCR5 aggravates myocardial I/R injury through modulating inflammatory responses in rat heart.
Highlights
Reperfusion strategies have substantially contributed to the effective treatment of ischemic heart diseases despite the potential negative impact of ischemia/reperfusion (I/R) injury[1]
Our results suggest that blocking chemokine receptor 5 (CCR5) attenuates while enhancing CCR5 aggravates myocardial ischemia– reperfusion (I/R) injury through modulating inflammatory responses in rat heart
CCR5 antibody and CCR5 agonist RANTES were purchased from Sigma (USA); creatine kinase (CK) and myeloperoxidase (MPO) kit were purchased from Nanjing Jiancheng Bioengineering Institute (China)
Summary
Reperfusion strategies have substantially contributed to the effective treatment of ischemic heart diseases despite the potential negative impact of ischemia/reperfusion (I/R) injury[1]. It is known that increased chemokine expression post I/R could promote the adhesion of neutrophils and increase leukocyte infiltration in the cardiac tissue [6], which could serve as one of the important mechanisms mediating the ischemic myocardial damage. CC-chemokine receptor 5 (CCR5) is expressed on T-lymphocytes with memory/effector phenotype, macrophages, monocytes, as well as the immature dendritic cells [8]. Previous study showed that TAK-779, a small-molecule, nonpeptide compound that selectively binds to a certain subtype of the CC-chemokine receptor, CCR5, with high affinity [10], could effectively reduce leukocyte infiltration of the reperfused tissue and attenuate subsequent postischemic organ failure in mouse models of focal cerebral ischemia [11]. We tested the hypothesis that myocardial I/R injury could be attenuated by CCR5 antibody or aggravated by CCR5 agonist RANTES in rats
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