Abstract 3395: The Homeostatic Chemokine CXCL13 and Its Receptor CXCR5 Are Regulated in Heart Failure and Are Involved in Cardiac Remodelling
The chemokine CXCL13 and its receptor CXCR5 are crucial for lymphocyte trafficking, also in non-lymphatic tissue. Since inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), we hypothesized that CXCL13/CXCR5 could be involved in this process. We found increased plasma levels of CXCL13 in HF patients corresponding to NYHA class (n=110), accompanied by enhanced mRNA levels of CXCR5 in circulating T cells (14%, p<0.01). In an experimental mouse model of HF secondary to pressure overload (aortic banding, AB), we found a threefold increase (p<0.01) in gene expression of CXCR5 in the hypertrophic left ventricle (LV) compared to sham-operated mice. To further examine the role of CXCL13 and CXCR5 in myocardial remodeling and development of HF, we exposed CXCR5 deficient (CXCR5 KO) and wild type (WT) mice to AB for 3 weeks. Echocardiography demonstrated substantially increased LV inner diameter in CXCR5 KO as compared to WT mice (5.00±0.24 mm vs. 4.31±0.12 mm, p<0.05). Heart weight was similar in the two groups, but the thickness of the LV posterior wall (0.70±0.06 mm vs. 1.10±0.09 mm, p<0.05) and interventricular wall (0.77±0.06 vs. 0.98±0.07 mm, p<0.05) was significantly reduced in CXCR5 KO compared to WT mice. The dilatation of the LV in CXCR5 KO mice was accompanied by a significant increase in gene expression of ANP, BNP and α-MHC (p<0.05 for all), reflecting enhanced wall stress and possibly accelerated remodelling. Moreover, we found increased infiltration of CD45R+ cells in AB CXCR5 KO mice together with increased total MMP activity (24%, p<0.01) and decreased TIMP 3 levels (47%, p<0.01), suggesting enhanced matrix degradation in CXCR5 KO mice. Microarray analysis (Affymetrix) revealed altered expression of a large number of genes encoding proteins found in the extracellular matrix. In conclusion, our data demonstrate that the homeostatic chemokine CXCL13 and its receptor CXCR5 are regulated in experimental and human HF. Furthermore, we show that lack of CXCR5 leads to LV dilatation and wall thinning, possibly via altered infiltration of inflammatory cells and alterations in the composition of the extracellular matrix.