© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Myocardial expression of CC- and CXC-chemokines and their receptors in human end-stage heart failure
aDepartment of Cardiology, Division of Heart and Lung Diseases, The National Hospital, Oslo, Norway
bDepartment of Cardiothoracic Surgery, Division of Heart and Lung Diseases, The National Hospital, Oslo, Norway
cResearch Institute for Internal Medicine, The National Hospital, University of Oslo, Oslo, Norway
dSection of Clinical Immunology and Infectious Diseases, Medical Department, The National Hospital, Oslo, Norway
eSection of Endocrinology, Medical Department, The National Hospital, Oslo, Norway
fMSD-Cardiovascular Research Center, The National Hospital, Oslo, Norway
gInstitute for Experimental Medical Research, Ullevål Hospital, University of Oslo, Oslo, Norway
* Corresponding author. Tel.: +47-230-736-28; fax: +47-230-736-30 j.k.damas{at}klinmed.uio.no
Received 10 February 2000; accepted 15 May 2000
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 Discussion5 ConclusionReferences |
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Objectives: Chemokines regulate several biological processes, such as chemotaxis, collagen turnover, angiogenesis and apoptosis. Based on the persistent immune activation with elevated circulating levels of chemokines in patients with congestive heart failure (CHF), we have hypothesised a pathogenic role for chemokines in the development of CHF. The objective of this study was to examine mRNA levels and cellular localisation of chemokines and chemokine receptors in human CHF. Methods: We examined explanted hearts from ten patients with end-stage heart failure (all chambers) and in ten organ donors using an RNase protection assays and immunohistochemical techniques. Results: Our main findings were: (i) expression of eight chemokine and nine chemokine receptor genes in both failing and nonfailing myocardium, (ii) particularly high mRNA levels of monocyte chemoattractant protein (MCP)-1 and CXC-chemokine receptor 4 (CXCR4), in both chronic failing and nonfailing myocardium, (iii) decreased mRNA levels of MCP-1 and interleukin (IL)-8 in the failing left ventricles compared to failing left atria, (iv) decreased chemokine (e.g., MCP-1 and IL-8) and increased chemokine receptor (e.g., CCR2, CXCR1) mRNA levels in failing left ventricles and failing left atria compared to corresponding chambers in the nonfailing hearts and (v) immunolocalisation of MCP-1, IL-8 and CXCR4 to cardiomyocytes. Conclusion: The present study demonstrates for the first time chemokine and chemokine receptor gene expression and protein localisation in the human myocardium, introducing a new family of mediators with potentially important effects on the myocardium. The observation of chemokine dysregulation in human end-stage heart failure may represent a previously unknown mechanism involved in progression of chronic heart failure.
KEYWORDS Cytokines; Gene expression; Heart failure; Infection/inflammation; Monoclonal antibodies
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1 Introduction |
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Inflammatory processes seem to be involved in the pathogenesis and progression of congestive heart failure (CHF). Previous studies have shown that inflammatory cytokines, e.g., tumor necrosis factor (TNF)-
, interleukin (IL)-1 and IL-6-related cytokines, may induce myocardial dysfunction [1,2] and cardiac remodelling through mechanisms such as promotion of cardiomyocyte hypertrophy [3] and apoptosis [4], as well as alternation in extracellular matrix in the myocardium [5]. Chemokines represent a family of inflammatory cytokines that control chemotaxis of leukocyte subsets into inflamed tissue [6]. While CC-chemokines are potent chemoattractants and activators for monocytes and lymphocytes, most CXC-chemokines attract neutrophils [7]. However, in addition to chemotaxis, several functional responses, including adherence to endothelium, enzyme secretion and induction of respiratory burst, are observed in vitro after chemokine stimulation of these leukocyte subsets [8,9].
So far, some studies have suggested a role for chemokines in the pathogenesis of various heart diseases, such as atherosclerosis [10], myocarditis [11] and reperfusion damage of ischemic myocardium [12]. Recently, we have demonstrated elevated circulating levels and enhanced release from monocytes and platelets of both CC- and CXC-chemokines in CHF [13,14], suggesting a possible pathogenic role of these mediators also in the progression of heart failure. Indeed, chronic low-grade inflammation, as reflected in activated vascular endothelium and the presence of infiltrating inflammatory cells, has been found in the failing myocardium [15]. Chemokines may be important mediators in this process by promoting attraction and invasion of activated leukocytes. Furthermore, recent reports indicate that, besides being potent inducers of chemotaxis and leukocyte activation, chemokines may have several other biological properties with relevance to the pathogenesis of heart failure, such as induction of cell proliferation and involvement during organogenesis [16] and cardiogenesis [17]. Based on the possible pathogenic role of chemokines in the development and progression of heart failure, we have examined myocardial gene expression and cellular localisation of chemokines and their corresponding receptors in human end-stage heart failure.
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2 Methods |
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2.1 Patients and myocardial tissue samples
Studies were performed in accordance with institutional human studies guidelines and conform with the principles outlined in the Declaration of Helsinki. Explanted hearts (left and right ventricles and atria) from ten patients with end-stage CHF [coronary artery disease (CAD), n=7; idiopathic dilated cardiomyopathy (IDCM), n=2; valvular heart disease, n=1] undergoing heart transplantation were used in the study (seven men and three women; aged 21 to 57 years; mean, 45.6±3.5 years). All patients were in NYHA functional classes III and IV, and all had a left ventricular ejection fraction (EF) <35%. All were treated with angiotensin converting enzyme inhibitors, 60% with digitoxin, 60% with β-blockers, but none were receiving intravenous ionotropic support before transplantation. Nonfailing human heart tissue was obtained from suitable heart donors (left atria, n=6) and from subjects whose hearts were rejected for cardiac donation because of functional criteria or no recipient available (left ventricles, n=4). The cause of death of the donors was acute cerebrovascular accident or trauma, and none of the organ donors had a history of heart failure. The nonfailing hearts were obtained from six men and four women, aged 19 to 45 years (mean, 37.9±3.6 years). In addition, total RNA extracted from human heart tissue was obtained from Clontech (Palo Alto, CA, USA). Clinical, demographic and hemodynamic data of the CHF study population are presented in Table 1.
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Tissue aliquots from the failing myocardium of cardiac recipients were removed from the still-contracting hearts immediately after explantation, and immersed in liquid nitrogen before storage at –80°C until use. Care was taken not to sample scarred, fibrotic, or adipose tissue, endocardium, epicardium, or great vessels. Routine histology was performed in all explanted hearts and there were no signs of acute or chronic myocarditis in any of the hearts included in the study. Hearts from actual donors and from subjects rejected as heart donors were kept on iced water for 42 to 206 min (mean ischemic time, 122±32 min) before tissue was processed as described above.
2.2 RNA preparation
Total RNA was extracted from frozen atrial and ventricular tissue using a modification of the acid guanidinium thiocyanate (GTC)–phenol–chloroform method [18]. Briefly, the frozen tissue was minced in liquid nitrogen, placed in GTC-solution and homogenised with an Ultra-Turrax homogeniser for 30 s. Subsequently, 2 mol/l sodium acetate, pH 4, and chloroform–phenol, 5:1 (v/v), pH 4, were added. The mixture was shaken vigorously. After centrifugation (12,000 g for 20 min), the aqueous phase was collected, and the RNA was precipitated by the addition of an equal volume of isopropanol. A double extraction and DNase I treatment (RQI DNase, Promega, Madison, WI, USA) was routinely used to eliminate small amounts of DNA contamination. The RNA pellet was washed with 75% ethanol and resuspended in RNA storage solution (Ambion, Austin, TX, USA) and stored at –80°C until used. The integrity of the extracted total RNA was assessed by agarose gel electrophoresis and ethidium bromide staining. RNA concentration and purity were evaluated in duplicate by measuring the absorbance at 260/280 nm using a spectrophotometer (GeneQuant; Pharmacia, Uppsala, Sweden).
2.3 RNase protection assay (RPA)
RPA was used for the detection and quantification of mRNA species. Multi-probes hCK5 (eight chemokine probes), hCR5 (eight CC-chemokine receptor probes) and hCR6 (seven CXC-chemokine receptor probes) were available with reagents for in vitro transcription and RPA (RiboQuant; Pharmingen, San Diego, CA, USA). The following anti-sense RNA probes, which were able to hybridise with target human mRNA, were synthesised: lymphotactin (Ltn), regulated on activation normally T-cell expressed and secreted (RANTES), interferon 
-inducible protein (IP)-10, macrophage inflammatory protein (MIP)-1 and -1β, MCP-1, IL-8 and inducible (I)-309, the CC-chemokine receptors (CCR)1–5, TER1 (CCR8), the CXC-chemokine receptors (CXCR)1–4, Burkitt's lymphoma receptor (BLR)-1, -2, V28 (CX3CR) and ribosomal protein (rp) L32, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
For all hybridisation assays, 
2 µg total RNA from each patient or donor sample were mixed with 0.5–2x106 cpm of probe (-32P-UTP, 3000 Ci/mmol). Protected fragments were separated in a denaturing 6% polyacrylamide gel for 90 min. The dried gel was exposed to a phosphorimaging screen (Cyclone system; Packard, Meriden, CT, USA) for 20 h followed by densitometric analysis using 1D Quantifier (Phoretix, Newcastle, UK). A quantitative estimate of the mRNA levels for chemokines and chemokine receptors was attempted by comparing the results with the mRNA levels of rpL32 and GAPDH genes. The intra-experimental coefficients of variation (C.V.) were 13.4% (rpL32, n=20) and 15.2% (GAPDH, n=20).
2.4 Immunohistochemistry
Heart tissue from failing hearts (left ventricles and atria) and from nonfailing hearts (left atria) were fixed with 4% paraformaldehyde and embedded in paraffin wax. The paraffin-embedded myocardial tissue was cut into 7-µm sections, dewaxed in xylene, and subsequently rehydrated in descending concentrations of ethanol. The sections were blocked with normal horse serum and subsequently incubated with mouse monoclonal anti-human IL-8, anti-human MCP-1 or anti-human CXCR4 antibodies (R&D Systems, Minneapolis, MD, USA). To block the presence of endogenous peroxidase activity, the slides were incubated with 0.3% hydrogen peroxide in methanol for 30 min at room temperature and were washed in phosphate-buffered saline (PBS) for 5 min. Anti-IL-8, anti-MCP-1 and anti-CXCR4 immunoreactivity were amplified by the avidin–biotin–peroxidase system (Vectastain Elite kit, Vector laboratories, Burlingame, CA, USA) according to the manufacturer's instructions. Briefly, the sections were incubated with biotinylated horse anti-mouse IgG for 30 min at room temperature, washed in PBS, and incubated with the avidin–biotin–peroxidase complex for 30 min. After a final wash in PBS, the slides were incubated with diaminobenzidine as the chromogen in a commercial metal-enhanced system (Pierce Chemical), and the sections were counterstained with hematoxylin. Omission of primary antibody and replacing it with nonimmune mouse IgG served as the negative control. In addition, sections were stained with van Gieson to identify extracellular collagen in the myocardium.
2.5 Statistical analysis
For comparison between different individuals or cardiac chambers, one-way ANOVA and the Bonferonni multiple comparison procedure were used. Data were log-transformed when not normally distributed. Probability values are considered significant when P<0.05. Data are expressed as mean±S.E.M. if not otherwise stated. Analysis utilised the computer program PRISM (GraphPad, San Diego, CA, USA).
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 ConclusionReferences |
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3.1 Gene expression of chemokines and chemokine receptors in the human myocardium
RPA was used to detect and quantify chemokine and chemokine receptor mRNA abundance in total RNA extracted from explanted failing (n=10; four chambers, i.e. 40 samples) and nonfailing hearts (n=10; six left atria, four left ventricles). Out of 23 different chemokine and chemokine receptor genes tested, 17 were detected in both failing and nonfailing hearts using RPA (Fig. 1A–C). These genes were expressed at different levels in all chambers of the failing hearts. The relative levels of gene expression in both failing and nonfailing hearts were highest for MCP-1, IL-8, RANTES and MIP-1
, representing both CC- and CXC-chemokines (Fig. 1 and Table 2). Furthermore, the CC-chemokine receptors CCR1, CCR2, CCR4 and CCR5, and the CXC-chemokine receptors CXCR1, CXCR2, V28 and CXCR4 were expressed in both failing and nonfailing hearts (Fig. 1 and Table 2). Notably, MCP-1 mRNA levels were up to fivefold higher than for any other chemokines, and CXCR4 was clearly the highest expressed chemokine receptor gene (Table 2).
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3.2 Quantitative assessment of chemokine and chemokine receptor gene expression in failing and nonfailing myocardium
Several significant differences between chemokine and chemokine receptor gene expression in failing and nonfailing hearts (left ventricles and atria) were observed. First, MCP-1, IL-8, RANTES and MIP-1
mRNA levels were significantly lower in failing left ventricles and atria compared to corresponding chambers in the nonfailing hearts (Fig. 2). Second, while MCP-1 and IL-8 mRNA expression were significantly raised in left atria compared to left ventricles (see below), no differences in chemokine mRNA expression between these chambers were found in the nonfailing hearts (Fig. 2). Finally, in contrast to chemokine mRNA levels, chemokine receptor mRNA expression, represented by CCR1, CCR2 and CXCR1, was significantly increased in both left ventricles and atria from failing myocardium compared to samples from nonfailing hearts (Fig. 3). Similar patterns of gene expression were also found for CCR4, CCR5, V28, CXCR2 (data not shown) and CXCR4 (Fig. 3), comparing failing and nonfailing hearts, although the differences did not reach statistical significance. In contrast, the expression of rpL32 relative to GAPDH was stable between failing and nonfailing myocardium and very similar results were found on analysing chemokine and chemokine receptor genes relative to the second control gene GAPDH (Fig. 4, see also Methods).
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3.3 Quantitative assessment of chemokine and chemokine receptor gene expression in different chambers of the failing heart
Several differences were detected in both chemokine and chemokine receptor mRNA levels between the cardiac chambers in the failing myocardium. MCP-1 (Figs. 2A and 5A
) and IL-8 (Fig. 2B) mRNA levels were significantly elevated in the left atria compared to left ventricles in the failing hearts. Similar patterns of gene expression were found for RANTES and MIP-1, although the differences did not reach statistical significance (Table 2). Variations in gene expression between cardiac chambers were also found for chemokine receptor mRNA levels, although a systematic difference between left atria and left ventricles was absent (Fig. 5B and Table 2). However, the mRNA expression of the receptors CXCR1 and CXCR2 was significantly higher (P<0.01) and tended to be higher for CCR2 and CXCR4 in the left compared to right ventricles (Table 2). In contrast to these variations in chemokine and chemokine receptor mRNA expression according to anatomical site, the variation in mRNA levels of the housekeeping genes for rpL32 and GAPDH were almost similar to the intra-experimental C.V., indicating stable expression in heart failure and equal cellular content in the myocardial samples.
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3.4 Immunohistochemical analysis
Cellular localisation was investigated for the highest expressed CC-, CXC-chemokine and chemokine receptor gene (MCP-1, IL-8 and CXCR4, respectively) in left ventricles and atria from failing and in left atria from nonfailing hearts. Immunohistochemical analysis of the myocardium revealed IL-8-like immunoreactivity (IL-8-ir), MCP-1-ir and CXCR4-ir in left atria and left ventricles of failing hearts and in left atria of nonfailing hearts (Fig. 6). Cardiomyocytes and the vascular smooth muscle cells displayed IL-8-ir, MCP-1-ir and CXCR4-ir. Histochemical analysis using van Gieson revealed myocardial deposition of collagen predominantly in perivascular tissue and these areas were not immunoreactive to either IL-8, MCP-1 or CXCR4. The degree of anti-CXCR4 and anti-MCP-1 immunostaining was consistent with the mRNA levels showing increased CXCR4-ir and decreased MCP-1-ir in failing compared to nonfailing myocardium. Furthermore, MCP-1-ir was higher in atria compared to ventricles in the failing heart. As for IL-8-ir, there were only minor differences between failing and nonfailing myocardium. Omitting primary antibody and replacing it with non-immune IgG abolished the signals, demonstrating specificity of the IL-8, MCP-1 and CXCR4 antibodies.
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 ConclusionReferences |
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The present study is the first to demonstrate that the human myocardium, both under failing and nonfailing conditions, expresses significant levels of several CC- and CXC-chemokines and their corresponding receptors, with particularly high levels of MCP-1 and CXCR4. This was confirmed at both gene and corresponding protein levels. Finally, by immunohistochemistry, we demonstrated that the chemokines MCP-1 and IL-8 and the chemokine receptor CXCR4 are located to the cardiomyocytes and not only to ‘contaminating’ leukocytes, endothelial cells or fibroblasts. Chemokines have recently attracted considerable attention as important mediators of inflammation and host defence. Our findings in the present study suggest that the ‘chemokine system’ also may represent a previously unrecognised factor in the pathogenesis of heart failure.
Although chemokines are normally considered beneficial in wound healing, hematopoiesis, organogenesis and in the clearance of infectious organisms [16,17], dysregulated expression of chemokines has been associated with chronic inflammatory conditions such as atherosclerosis [10], arthritis [19], bronchial asthma [20], and inflammatory bowel syndrome [21]. Several reports indicate a role for immunologic and inflammatory processes in the pathogenesis of CHF [1–5,13,14]. We would like to suggest that chemokines may be important mediators in this process by promoting attraction and invasion of activated leukocytes into the failing myocardium. Indeed, interstitial monocyte infiltration in the myocardium with development of a number of pathological changes characterising CHF, including cardiac hypertrophy, ventricular dilatation and depressed contractile function, is found in transgenic mice with myocardial over-expression of MCP-1 [11]. Some of these pathological changes may be caused by the ability of MCP-1, as well as other chemokines, to induce production of proteolytic enzymes, reactive oxygen species and inflammatory cytokines in recruited myocardial monocytes [22–24]. However, the present study suggests that the cardiomyocytes themselves also may have an active role in inflammatory processes, not only by producing several chemokines and in particular MCP-1, but also by expressing several chemokine receptors of both the CC and CXC subtypes.
Although the primary function of chemokines is thought to be recruitment of circulating leukocytes into sites of inflammation, recent studies suggest that chemokines may also mediate other biological effects, such as cell proliferation [17], collagen turnover [25], modulation of matrix metalloproteinase activity [26], angiogenesis [27] and induction of apoptosis [28]. Several of these are clearly of interest with regard to the pathogenesis of heart failure. Thus, although there are no reports of direct chemokine-mediated effects on cardiomyocytes, our novel findings of both CC- and CXC-chemokine receptor mRNA expression in human myocardium, with particularly high levels of CXCR4 and anti-CXCR4 immunostaining of cardiomyocytes, suggest that chemokines may directly modulate cardiomyocyte function. The observation of embryonic lethality and developmental defects, including cardiac ventricular septum defects in CXCR4 knock-out mice, indicates a direct chemokine-mediated effect on the myocardium [29]. Furthermore, enhanced cardiomyocyte apoptosis appears to be involved in the pathogenesis of end-stage CHF [30] and, notably, CXCR4 may trigger apoptosis in various cell types [28,31,32], underscoring the pathogenic potential of our findings of CXCR4 expression in the failing left ventricle. Finally, the myocardial expression of chemokine receptors is also of interest with regard to the development of dilated cardiomyopathy in AIDS patients. By being co-receptors for human immunodeficiency virus (HIV) [33], CCR5 and CXCR4 may be of importance in permitting HIV entry into the myocardium, which recently has been demonstrated in AIDS-related cardiomyopathy [34]. Although further studies are needed to clarify the potential role of chemokines and their receptors in the pathogenesis of CHF, our discovery of a ‘chemokine network’ in the human heart, located to the cardiomyocytes, suggests that locally produced chemokines may directly exert an effect upon the myocardium, possibly working through an autocrine/paracrine mechanism.
Our comparison between failing and nonfailing hearts suggests downregulation of chemokine expression and upregulation of chemokine receptor expression in the end-stage failing myocardium. While MCP-1 and other chemokines may be upregulated in an earlier stage of heart failure [35], our findings suggest that these mediators are downregulated in the myocardium of patients with end-stage heart failure. In fact, a dynamic regulation of inflammatory mediators in the myocardium may well exist, with upregulation in acute heart failure and in the ‘hypertrophic phase’ of CHF, and with downregulation in decompensated CHF, characterised by a dilated left ventricle [36].
Caution is needed when comparing chemokine expression in failing and nonfailing myocardium. Individuals ‘donating’ control tissue may have been exposed to stressful stimuli and hypoxia before death. Chemokine genes are transcribed early upon activation [37], and hypoxia has been shown to be a potent inducer of chemokine gene expression [38]. Although we found no association between chemokine gene expression and ischemic time before donor tissue sampling, we cannot exclude some transcription of these genes before explantation in the donor group. Furthermore, the interpretation of chemokine protein expression is difficult taking into consideration the complexity of tissue-specific regulation of chemokine and chemokine receptor expression. Differences in the clearance of the chemokines by proteolysis could partly contribute the overall picture of differential tissue expression of chemokines [39]. Accordingly, further studies are needed to examine these aspects of chemokine regulation in myocardial tissue.
In the failing, but not in the nonfailing, myocardium, we found differences in the expression of chemokines between different chambers of the heart. In particular, the MCP-1 and IL-8 mRNA levels were higher in all failing left atria compared to failing left ventricles. We hypothesise that these findings may reflect differences between left atria and ventricles with regard to hemodynamic burden and ischemic exposure. Thus, while left ventricle in these patients represents end-stage myocardium with downregulated MCP-1 expression, left atria may possibly represent an ‘earlier stage’ of heart failure. Whatever the reasons, our observations clearly underscore the importance of studying different chambers individually when comparing failing and nonfailing myocardium.
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5 Conclusion |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 ConclusionReferences |
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The present study demonstrates for the first time chemokine and chemokine receptor mRNA expression and protein synthesis in the human myocardium, with CC- and CXC-chemokines, and chemokine receptors located to the cardiomyocytes. The observation that the end-stage failing heart expresses decreased levels of chemokines and increased levels of chemokine receptors may represent one of several different maladaptive mechanisms responsible for progression of advanced heart failure. The ‘chemokine system’ may represent a previously unrecognised pathogenic factor in the development of CHF and may introduce a new family of mediators with potentially important effects on the myocardium.
Time for primary review 28 days.
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Acknowledgements |
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This work was supported by the Norwegian Council of Cardiovascular Disease, Research Council of Norway and Medinnova Foundation. We thank Anne Brunsvig for excellent technical assistance.
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References |
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TopAbstract1 Introduction2 Methods3 Results4 Discussion5 ConclusionReferences |
|---|
- Finkel M.S., Oddis C.V., Jacob T.D., et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science (1992) 257:387–389.
[Abstract/Free Full Text] - Yokoyama T., Vaca L., Rossen R.D., et al. Cellular basis for the negative inotropic effects of tumor necrosis factor- in the mammalian heart. J Clin Invest (1993) 92:2303–2312.[Web of Science][Medline]
- Hirota H., Yoshida K., Kishimoto T., Taga T. Continuous activation of GP 130, a signal-transacting receptor component for interleukin-6 related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci USA (1995) 92:4862–4866.
[Abstract/Free Full Text] - Krown K.A., Page M.T., Nguyen C., et al. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. J Clin Invest (1996) 98:2854–2865.[Web of Science][Medline]
- Bozkurt B., Kribbs S.B., Clubb F.J. Jr., et al. Pathophysiologically relevant concentrations of tumor necrosis factor- promote progressive left ventricular dysfunction and remodeling in rats. Circulation (1998) 97:1382–1391.
[Abstract/Free Full Text] - Taub D.D., Oppenheim J.J. Chemokines, inflammation and the immune system. Ther Immunol (1994) 1:229–246.[Medline]
- Bagglioni M., Dewald B., Moser B. Interleukin-8 and related chemotactic cytokines: CXC and CC-chemokines. Adv Immunol (1994) 55:97–179.[Web of Science][Medline]
- Jaeschke H., Smith C.W. Mechanisms of neutrophil-induced parenchymal cell injury. J Leukoc Biol (1997) 61:647–653.[Abstract]
- Waltz A., Meloni F., Clark-Lewis I., von Tscharner V., Baggiolini M. [Ca2+]i changes and respiratory burst in human neutrophils and monocytes induced by NAP-1/Interleukin-8, NAP-2 and gro/MGSA. J Leukoc Biol (1991) 50:279–286.[Abstract]
- Boring L., Gosling J., Clearl M., Charo I.F. Decreased lesion formation in CCR2–/– mice reveals a role for chemokines in the initiation of atherosclerosis. Nature (1998) 394:894–897.[CrossRef][Medline]
- Kolattukudy P.E., Quach T., Bergese S., et al. Myocarditis induced by targeted expression of the MCP-1 gene in murine cardiac muscle. Am J Pathol (1998) 152:101–111.[Abstract]
- Kukielka G.L., Youker K.A., Michael L.H., et al. Role of early reperfusion in the induction of adhesion molecules and cytokines in previously ischemic myocardium. Mol Cell Biochem (1995) 147:5–12.[CrossRef][Web of Science][Medline]
- Aukrust P., Ueland T., Müller F., et al. Elevated circulating levels of C-C chemokines in patients with congestive heart failure. Circulation (1998) 97:1136–1143.
[Abstract/Free Full Text] - Damås J.K., Gullestad L., Ueland T., et al. CXC-chemokines, a new group of cytokines in congestive heart failure—possible role of platelets and monocytes. Cardiovasc Res (2000) 45:428–436.
[Abstract/Free Full Text] - Devaux B., Scholz D., Hirche A., Klovekorn W.P., Schaper J. Upregulation of cell adhesion molecules and the presence of low grade inflammation in human chronic heart failure. Eur Heart J (1997) 18:470–479.
[Abstract/Free Full Text] - Luster A.D. Chemokines—chemotactic cytokines that mediate inflammation. N Engl J Med (1998) 338:436–445.
[Free Full Text] - Nagasawa T., Hirota S., Tachibana K., et al. Defect of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature (1996) 382:635–638.[CrossRef][Medline]
- Chomezynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem (1987) 162:156–159.[Web of Science][Medline]
- Barnes D.A., Tse J., Kaufhold M., et al. Polyclonal antibody directed against human RANTES ameliorates disease in the Lewis rat adjuvant-induced arthritis model. J Clin Invest (1998) 101:2910–2919.[Web of Science][Medline]
- Lamkhioued B., Renzi P.M., Abi-Younes S. Increased expression of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation. J Immunol (1997) 159:4593–4601.[Abstract]
- Z’Graggen K., Walz A., Mazzucchelli L., Strieter R.M., Mueller C. The C-X-C chemokine ENA-78 is preferentially expressed in intestinal epithelium in inflammatory bowel disease. Gastroenterology (1997) 113:808–816.[CrossRef][Web of Science][Medline]
- Vonhof S., Brost B., Stille-Siegener M., et al. Monocyte activation in congestive heart failure due to coronary artery disease and idiopathic dilated cardiomyopathy. Int J Cardiol (1998) 63:237–244.[CrossRef][Web of Science][Medline]
- Rollins B.J., Walz A., Baggiolini M. Recombinant MCP-1/JE induces chemotaxis, calcium flux, and respiratory burst in human monocytes. Blood (1991) 78:1112–1116.
[Abstract/Free Full Text] - Buttke T.M., Sandstrom P.A. Oxidative stress as a mediator of apoptosis. Immunol Today (1994) 15:7–10.[CrossRef][Web of Science][Medline]
- Unemori E.N., Amento E.P., Bauer E.A., Horuk R. Melanoma growth-stimulatory activity/GRO decreases collagen expression by human fibroblasts. J Biol Chem (1993) 268:1338–1342.
[Abstract/Free Full Text] - Unemori E.N., Marsters J.C., Bauer E.A., Amento E.P. The product of the GRO gene regulates collagen turnover by inducing tissue inhibitor metalloproteinases. Arthritis Rheum (1991) 34:S117.
- Koch A.E., Polverini P.J., Kunkel S.L., et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science (1992) 258:1798–1801.
[Abstract/Free Full Text] - Hesselgesser J., Taub D., Baskar P., et al. Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1 alpha is mediated by the chemokine receptor CXCR4. Curr Biol (1998) 8:595–598.[CrossRef][Web of Science][Medline]
- Tachibana K., Hirota S., Ilizasa H., et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature (1998) 393:591–594.[CrossRef][Medline]
- Aukrust P., Gullestad L., Frøland S.S. Is apoptosis an important pathogenic factor in cardiovascular disease? Eur J Clin Invest (1999) 29:369–371.[CrossRef][Web of Science][Medline]
- Berndt C., Mopps B., Angermüller S., Gierschik P., Krammer P.H. CXCR4 and CD4 mediate CD95-independent cell death in CD4+ T cells. Proc Natl Acad Sci USA (1998) 95:12556–12561.
[Abstract/Free Full Text] - Herbein G., Mahlknecht U., Batliwalla F., et al. Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4. Nature (1998) 395:189–194.[CrossRef][Medline]
- Lu Z., Berson J.F., Chen Y., et al. Evolution of HIV-1 co-receptor usage through interaction with distinct CCR5 and CXCR4 domains. Proc Natl Acad Sci USA (1997) 94:6426–6431.
[Abstract/Free Full Text] - Barbaro G., Di Lorenzo G., Grisorio B., Barbarini G. Incidence of dilated cardiomyopathy and detection of HIV in myocardial cells of HIV-positive patients. N Engl J Med (1998) 339:1093–1099.
[Abstract/Free Full Text] - Shioi T., Matsumori A., Kihara Y., et al. Increased expression of interleukin-1β and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in hypertrophied and failing heart with pressure overload. Circ Res (1997) 81:664–671.
[Abstract/Free Full Text] - Ono K., Matsumori A., Shioi T., Furukawa Y., Sasayama S. Cytokine gene expression after myocardial infarction in rat hearts: possible implication in left ventricular remodeling. Circulation (1998) 98:149–156.
[Abstract/Free Full Text] - Freter R.R., Alberta J.A., Lam K.K., Stiles C.D. A new platelet-derived growth factor-regulated genomic element which binds serine/threonine phosphoprotein mediates induction of the slow immediately-early gene MCP-1. Mol Cell Biol (1995) 15:315–325.[Abstract]
- Karakurum M., Shreeniwas R., Chen J., et al. Hypoxic induction of interleukin-8 gene expression in human endothelial cells. J Clin Invest (1994) 93:1564–1570.[Web of Science][Medline]
- Devalaraja M.N., Richmond A. Multiple chemotactic factors: fine control or redundancy? Trends Pharmacol Sci (1999) 20:151–156.[CrossRef][Medline]
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 E. C. Keeley, B. Mehrad, and R. M. Strieter Chemokines as Mediators of Neovascularization Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1928 - 1936. [Abstract] [Full Text] [PDF]
|
|
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|
 P. Misra, D. Lebeche, H. Ly, M. Schwarzkopf, G. Diaz, R. J. Hajjar, A. D. Schecter, and J. V. Frangioni Quantitation of CXCR4 Expression in Myocardial Infarction Using 99mTc-Labeled SDF-1{alpha} J. Nucl. Med., June 1, 2008; 49(6): 963 - 969. [Abstract] [Full Text] [PDF]
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 C Stumpf, C Lehner, D Raaz, A Yilmaz, T Anger, W G Daniel, and C D Garlichs Platelets contribute to enhanced MCP-1 levels in patients with chronic heart failure Heart, January 1, 2008; 94(1): 65 - 69. [Abstract] [Full Text] [PDF]
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 Y. Li, G. Takemura, H. Okada, S. Miyata, R. Maruyama, L. Li, M. Higuchi, S. Minatoguchi, T. Fujiwara, and H. Fujiwara Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure Cardiovasc Res, September 1, 2006; 71(4): 684 - 694. [Abstract] [Full Text] [PDF]
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A. Yndestad, A. M Holm, F. Muller, S. Simonsen, S. S Froland, L. Gullestad, and P. Aukrust Enhanced expression of inflammatory cytokines and activation markers in T-cells from patients with chronic heart failure Cardiovasc Res, October 15, 2003; 60(1): 141 - 146. [Abstract] [Full Text] [PDF]
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