Cytokine expression profiling of the myocardium reveals a role for CX3CL1 (fractalkine) in heart failure.
Several lines of evidence suggest that inflammatory processes mediated by cytokines are involved in the pathogenesis of heart failure (HF). However, the regulation of cytokine expression and the role of cytokines during HF development are not well understood. To address this issue, we have examined alterations in gene expression during HF progression by microarray technology in non-infarcted left ventricular (LV) murine tissue at various time points after myocardial infarction (MI). The highest number of regulated genes was found five days after MI. In total, we identified 14 regulated genes encoding cytokines with no previous association to HF. The strongest up-regulation was found for the chemokine fractalkine (CX3CL1). In human failing hearts we detected a 3-fold increase in CX3CL1 protein production, and both cardiomyocytes and fibrous tissue revealed immunoreactivity for CX3CL1 and its specific receptor CX3CR1. We also found that the circulating level of CX3CL1 was increased in patients with chronic HF in accordance with disease severity (1.6-fold in NYHA II, 2.2-fold in NYHA III and 2.9-fold in NYHA IV). In vitro experiments demonstrated that CX3CL1 production could be induced by inflammatory cytokines known to be highly expressed in HF. CX3CL1 itself induced the expression of markers of cardiac hypertrophy and protein phosphatases in neonatal cardiomyocytes. Given the increased CX3CL1 production in both an experimental HF model and in patients with chronic HF as well as its direct effects on cardiomyocytes, we suggest a role for CX3CL1 and its receptor CX3CR1 in the pathogenesis of HF.
Husberg
Cathrine
C
Institute for Experimental Medical Research, Ullevaal University Hospital, Oslo, Norway.
Nygård
Ståle
S
Finsen
Alexandra Vanessa
AV
Damås
Jan Kristian
JK
Frigessi
Arnoldo
A
Oie
Erik
E
Waehre
Anne
A
Gullestad
Lars
L
Aukrust
Pål
P
Yndestad
Arne
A
Christensen
Geir
G
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000235:genetics
D054428:Chemokine CX3CL1