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. 2007 Mar;85(3):257-71.
doi: 10.1007/s00109-006-0122-9. Epub 2006 Nov 15.

Genomic expression profiling of human inflammatory cardiomyopathy (DCMi) suggests novel therapeutic targets

F Wittchen  1 , L Suckau, H Witt, C Skurk, D Lassner, H Fechner, I Sipo, U Ungethüm, P Ruiz, M Pauschinger, C Tschope, U Rauch, U Kühl, H-P Schultheiss, W Poller
Affiliations

Genomic expression profiling of human inflammatory cardiomyopathy (DCMi) suggests novel therapeutic targets

F Wittchen et al. J Mol Med (Berl). 2007 Mar.

Abstract

The clinical phenotype of human dilated cardiomyopathy (DCM) encompasses a broad spectrum of etiologically distinct disorders. As targeting of etiology-related pathogenic pathways may be more efficient than current standard heart failure treatment, we obtained the genomic expression profile of a DCM subtype characterized by cardiac inflammation to identify possible new therapeutic targets in humans. In this inflammatory cardiomyopathy (DCMi), a distinctive cardiac expression pattern not described in any previous study of cardiac disorders was observed. Two significantly altered gene networks of particular interest and possible interdependence centered around the cysteine-rich angiogenic inducer 61 (CYR61) and adiponectin (APN) gene. CYR61 overexpression, as in human DCMi hearts in situ, was similarly induced by inflammatory cytokines in vascular endothelial cells in vitro. APN was strongly downregulated in DCMi hearts and completely abolished cytokine-dependent CYR61 induction in vitro. Dysbalance between the CYR61 and APN networks may play a pathogenic role in DCMi and contain novel therapeutic targets. Multiple immune cell-associated genes were also deregulated (e.g., chemokine ligand 14, interleukin-17D, nuclear factors of activated T cells). In contrast to previous investigations in patients with advanced or end-stage DCM where etiology-related pathomechanisms are overwhelmed by unspecific processes, the deregulations detected in this study occurred at a far less severe and most probably fully reversible disease stage.

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Figures

Fig. 1
Fig. 1
Altered gene expression profile and regulatory networks in DCMi. a, c, e The networks altered in DCMi are displayed graphically as nodes (genes/gene products) and edges (biological relationships between the nodes). Human, mouse, and rat orthologs of a gene are stored as separate objects in the knowledge base but are represented as a single node in the network. The intensity of the node color indicates the degree of up- (red) or down- (green) regulation. Nodes are displayed using various shapes that represent the functional class of the gene product. Continuous edge lines indicate protein–protein interactions, broken edge lines changes at the transcriptional level. The software further displays various labels that describe the nature of the relationship between the nodes (e.g., B for binding, T for transcription). b, d, f Show cluster analyses of the genes within the networks in (a), (c), (e), respectively. Here, analogous to the networks, red color denotes upregulation, green color denotes downregulation of a gene, whereas the brightness of the color indicates the extent of deregulation
Fig. 2
Fig. 2
Cytokines regulating of APN and CYR61 in cardiovascular cells. We searched for possible triggers of cardiac APN and CYR61 deregulation in DCMi in both endothelial cells and cardiomyocytes. a, b Summarize real-time quantitative TaqMan PCR data on the regulatory potential of inflammatory cytokines in these cell cultures investigated as first approximation to the far more complex in vivo situation with multiple resident and infiltrating cell types (compare Fig. 3). a Endothelial cells expressed CYR61 and both APN receptors but no detectable amount of APN mRNA (data not shown). The inflammatory cytokines TNF-α and IFN-β induced CYR61 expression in these cells, whereas others showed no effect (IFN-γ) or even reduced CYR61 (TNF-β). To reveal possible interactions between the APN and CYR61 regulatory networks, CYR61 induction experiments were conducted in the presence (asterisksin shaded bars) vs the absence of APN. The effect of APN on CYR61 induction by cytokines was unexpectedly strong: induction of CYR61 by TNF-α or IFN-β was not only abolished but reverted resulting in a net reduction of CYR61 expression below that in untreated controls. The APN concentration at which effect was observed is in the range 3–30 μg/ml as observed in human plasma [14]. Error bars indicate the SEM from two independent experiments each performed in triplicate. b In contrast to endothelial cells, cardiomyocytes expressed APN and its receptors as well as CYR61. Several inflammatory cytokines (TNF-α, IFN-β,γ) significantly reduced APN expression in cardiomyocytes, whereas CYR61 expression was not significantly altered in this cell type (not shown). Error bars as in panel (a)
Fig. 3
Fig. 3
Working model of local cardiac inflammation control. The model proposes the existence of a inflammation control system in human hearts acting by local synthesis of anti-inflammatory proteins, a representative of which is APN. If local cardiac APN synthesis by cardiomyocytes is genetically absent [38, 39] or suppressed (this study), inflammatory challenges may result in aggravated damage to endothelia and myocardium. This local model assumes that inflammation control and other regulatory functions are mediated by auto/paracrine actions of APN synthesized locally by cardiomyocytes, whereas in the context of APN knockout mice [38, 39], a complementary systemic model of APN action was proposed in which APN secreted by adipose tissue acts hormone-like to protect heart and endothelia via the circulation. APN (downregulated in DCMi) acts directly upon immune cells [10] (right side of figure) and also on nonimmune cells such as vascular endothelia [8] (left side). One new target for control by APN is CYR61 that is locally upregulated in DCMi (center) and whose endothelial induction by cytokines is suppressed by APN (see Fig. 2a). In addition to such direct anti-inflammatory action of APN on vascular endothelia (left side), APN is a potent negative regulator of IL-2-induced NK cell activation (right side) [10]. APN and cellular immunity are further linked by NFATs (upregulated in DCMi), which are key regulators of T cell function [54], and negative regulators of APN expression [9]. The functions of CYR61, APN, and other factors deregulated in DCMi in this local model are thought to be mediated via auto/paracrine loops unrelated to the respective circulating plasma levels. CYR61-associated CXCL14 downregulation in DCMi (right side) may alter immune cell attraction to the heart. IL-17D induction in DCMi (left side) may stimulate IL-6, IL-8, and GM-CSF production by endothelial cells and thus activation of the endothelium, the primary attachment site for migrating immune cells
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