Original articleCytokine expression profiling of the myocardium reveals a role for CX3CL1 (fractalkine) in heart failure
Introduction
Although treatment strategies for heart failure (HF) have improved over the last decades, this clinical syndrome is still a major cause of death. This indicates that important pathogenic mechanisms are not modified by the present treatment modalities [1]. Several lines of evidence suggest that persistent inflammation and immune activation could represent such mechanisms affecting development of HF [2], [3]. Moreover, the complex regulation of inflammatory mediators and their differential expression in myocardial tissue during HF development are far from completely understood. To address these issues, we have in this study performed microarray analysis of non-infarcted left ventricular (LV) tissue from mice subjected to left coronary artery ligation. In total, we discovered 14 cytokines which had not previously been assigned a role in HF progression.
CX3CL1 is a unique member of the CX3C chemokine subfamily and differs from most other cytokines in that it can function both as a circulating cytokine (soluble form) and in a membrane-bound form [4]. The full-length, membrane-bound form is thought to act mainly as an adhesion molecule promoting retention of leukocytes, while the soluble form resembles a conventional chemokine exhibiting chemotactic activity on monocytes, natural killer cells and T cells [4], [5]. In any form, the activity of CX3CL1 depends upon binding to the receptor CX3CR1, which originally was shown to be coupled to and act through pertussis toxin-sensitive Gαi protein [6]. Later, CX3CR1 has also been shown to signal through other G-proteins such as Gβγ[7], [8].
Previously, CX3CL1 has been suggested to play a role in atherogenesis [9] and two specific mutations in the CX3CR1 gene have been shown to be associated with reduced risk for future coronary events [10]. Furthermore, accumulating evidence indicates that CX3CL1/CX3CR1 are involved in the pathogenesis of other inflammatory disorders such as glomerulonephritis [11], rheumatoid arthritis [12], cardiac allograft rejection [13] and HIV infection [14]. To our knowledge, the potential role of CX3CL1 in the pathogenesis of myocardial hypertrophy or HF has not previously been studied.
Here we report that CX3CL1 synthesis is increased in cardiac tissue, not only in experimental HF, but also in the myocardium of HF patients. The increased myocardial production is accompanied by enhanced serum levels of CX3CL1, in accordance with disease severity. We also show that CX3CR1 is abundantly expressed in cardiomyocytes, and that CX3CL1 can act on cardiomyocytes to stimulate expression of genes involved in development of myocardial hypertrophy and HF.
Section snippets
Animal model of experimental HF
Myocardial infarction (MI) was induced in C57BL/6 mice (Taconic, Skensved, Denmark) [15], and the mice were sacrificed after 3, 5, 7 or 14 days. MI-mice included in the study had an infarcted area > 30% of total endocardial area in addition to significantly increased lung weight and left atrial diameter, indicating HF (see supplementary material) [15]. The animal experiments and housing were in accordance with institutional guidelines and national legislation. The study was approved by the local
Microarray screening for detection of regulated cytokines after MI
Alterations in gene expression in non-infarcted LV tissue following MI were analyzed at 3, 5, 7 and 14 days after ligation of the left coronary artery. Compared to the sham-operated animals, the mice with MI had a significant increase in lung weight, being highest at 14 days (see supplementary material). Similarly, LV fractional shortening was reduced and left atrial diameter was increased at all time points compared to the sham-operated animals, indicating cardiac failure in MI-mice. The
Discussion
A few other studies [26], [27] have examined gene expression in the non-infarcted myocardium with array technology at several time points after MI. While Stanton et al. [26] reported alterations in genes encoding cell signaling molecules and transcription factors, Sehl et al. [27] showed altered expression of genes involved in the wound healing process. Our study, focusing on inflammatory and anti-inflammatory mediators, explores alterations in expression of a larger number of genes in the
Acknowledgments
We thank Bjørg Austbø, Hilde Dishington, Geir Florholmen and Annlaug Ødegaard for excellent technical assistance.
References (41)
- et al.
Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion
Cell
(1997) - et al.
Phosphatidylinositol 3-kinase-dependent extracellular calcium influx is essential for CX(3)CR1-mediated activation of the mitogen-activated protein kinase cascade
J Biol Chem
(2001) - et al.
Signal transduction pathways involved in soluble fractalkine-induced monocytic cell adhesion
Blood
(2001) - et al.
A calcineurin-dependent transcriptional pathway for cardiac hypertrophy
Cell
(1998) - et al.
Increased expression of cardiac phosphatases in patients with end-stage heart failure
J Mol Cell Cardiol
(1997) Modulation of atherogenesis by chemokines
Trends Cardiovasc Med
(2004)- et al.
Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy
Am J Cardiol
(1999) - et al.
Neutralization of interleukin-1beta in the acute phase of myocardial infarction promotes the progression of left ventricular remodeling
J Am Coll Cardiol
(2001) - et al.
Spatial distribution of nerve sprouting after myocardial infarction in mice
Heart Rhythm
(2006) - et al.
The Akt-glycogen synthase kinase 3beta pathway regulates transcription of atrial natriuretic factor induced by beta-adrenergic receptor stimulation in cardiac myocytes
J Biol Chem
(2000)
p300 Functions as a coactivator of transcription factor GATA-4
J Biol Chem
Reduced Ca(2+)-sensitivity of SERCA 2a in failing human myocardium due to reduced serin-16 phospholamban phosphorylation
J Mol Cell Cardiol
Drug discovery for heart failure: a new era or the end of the pipeline?
Nat Rev Drug Discov
Targeted anticytokine therapy and the failing heart
Am J Cardiol
Therapeutic potential of anticytokine therapy in congestive heart failure
Am J Cardiovasc Drugs
A new class of membrane-bound chemokine with a CX3C motif
Nature
Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow
J Exp Med
Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, is elevated in coronary artery disease and is reduced during statin therapy
Arterioscler Thromb Vasc Biol
Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans
J Clin Invest
Fractalkine expression in human renal inflammation
J Pathol
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S.N. and A.V.F contributed equally to this work.