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Lack of chemokine signaling through CXCR5 causes increased mortality, ventricular dilatation and deranged matrix during cardiac pressure overload
- Source :
- PLoS ONE, PLoS ONE, Vol 6, Iss 4, p e18668 (2011), PLoS ONE 6 (4): e18668.
- Publication Year :
- 2010
-
Abstract
- Rationale Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. Objective We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. Methods and Results Mice harboring a systemic knockout of the CXCR5 (CXCR5−/−) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5−/− developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5−/− compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5−/− mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. Conclusions Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly.
- Subjects :
- Cancer Research
Chemokine
medicine.medical_specialty
Pathology
Decorin
Lumican
Heart Ventricles
Immunology
lcsh:Medicine
570 Life Sciences
Cardiovascular
CXCR5
610 Medical Sciences, Medicine
Extracellular matrix
Mice
Internal medicine
Molecular Cell Biology
medicine
Pressure
Animals
Electron Microscopy
CXCL13
lcsh:Science
Biology
Oligonucleotide Array Sequence Analysis
Pressure overload
Mice, Knockout
Heart Failure
Multidisciplinary
biology
Chemistry
lcsh:R
medicine.disease
Knockout Mice
Microscopy, Electron
Endocrinology
Heart failure
Immune System
biology.protein
Cytokines
Medicine
lcsh:Q
Chemokines
Signal Transduction
Research Article
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 6
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- PloS one
- Accession number :
- edsair.doi.dedup.....8937e557b250a1ad419f995a8ee8f200