Genomic expression profiling of human inflammatory cardiomyopathy (DCMi) suggests novel therapeutic targets.
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.
Wittchen
F
F
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12200, Berlin, Germany.
Suckau
L
L
Witt
H
H
Skurk
C
C
Lassner
D
D
Fechner
H
H
Sipo
I
I
Ungethüm
U
U
Ruiz
P
P
Pauschinger
M
M
Tschope
C
C
Rauch
U
U
Kühl
U
U
Schultheiss
H-P
HP
Poller
W
W
D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000628:therapy*; D055515:Cysteine-Rich Protein 61; D016207:Cytokines / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism
D052242:Adiponectin; C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D016207:Cytokines; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins