Abstract 489: CC Chemokine Receptor 5 Protects the Heart from Inflammation in Pressure Overload-induced Cardiac Dysfunction

Abstract

Objective: Sustained inflammation is a key pathological process in the development of heart failure and thus suppression of inflammation possibly leads to improvement of cardiac dysfunction. It has been suggested that CC chemokine receptor 5 (CCR5) scavenges pro-inflammatory mediators and resolves inflammation. The aim of this study is to uncover the role of CCR5 in the pathogenesis of heart failure. Methods: Pressure overload heart failure was induced by transverse aortic constriction (TAC). Sham or TAC operation was performed in male 10-week-old CCR5 knockout (KO) mice and wild-type (WT) controls. Cardiac function and morphology were examined by echocardiography 1 week and 4 weeks after TAC surgery. After euthanization, the heart was extracted and embedded in paraffin for the measurements of cardiac fibrosis and cardiomyocyte hypertrophy with EVG stain and immunohistochemistry using WGA, respectively. The extent of inflammation was evaluated by the immunostaining against CD45 and F4/80 antigens, and by qRT-PCR for inflammatory cytokines and chemokines. Results: We found that heart weight was significantly larger and fractional shortening was significantly lower in CCR5 KO mice than those in WT 4 weeks after TAC, indicating CCR5-induced protective effects on heart failure development. Whilst there was no difference observed in the extent of fibrosis, the size of cardiomyocytes from CCR5 KO heart tended to be increased compared to WT. The number of CD45-positive inflammatory cells and F4/80-positive macrophage infiltration was increased 1 week after TAC in KO mice. The RNA expression levels of monocyte chemotactic protein-1, transforming growth factor-β and tumor necrosis factor-α were significantly higher and NFκB p65 was more phosphorylated in KO mice. Conclusions: We revealed that the inflammation in pressure overload-induced heart failure was exacerbated by the deletion of CCR5 and, therefore, CCR5 could contribute to resolution of inflammation and be a potential therapeutic target for the heart failure treatment.