Lack of chemokine signaling through CXCR5 causes increased mortality, ventricular dilatation and deranged matrix during cardiac pressure overload |
| |
Authors: | Waehre Anne Halvorsen Bente Yndestad Arne Husberg Cathrine Sjaastad Ivar Nygård Ståle Dahl Christen P Ahmed M Shakil Finsen Alexandra V Reims Henrik Louch William E Hilfiker-Kleiner Denise Vinge Leif E Roald Borghild Attramadal Håvard Lipp Martin Gullestad Lars Aukrust Pål Christensen Geir |
| |
Institution: | Institute for Experimental Medical Research, Oslo University Hospital Ullev?l, Oslo, Norway. anne.waehre@medisin.uio.no |
| |
Abstract: | RationaleInflammatory 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.ObjectiveWe sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5
in cardiac pathophysiology leading to HF.Methods and ResultsMice 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.ConclusionsLack 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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|