Description of a local cardiac adiponectin system and its deregulation in dilated cardiomyopathy

Aims Despite recent advances in medical therapy, heart failure remains a leading cause for cardiovascular mortality, and its complex pathogenesis is incompletely understood. This study was performed to identify possible new therapeutic targets in dilated cardiomyopathy (DCM). Methods and results Oli...

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Bibliographic Details
Published in:European heart journal 2008-05, Vol.29 (9), p.1168-1180
Main Authors: Skurk, Carsten, Wittchen, Frank, Suckau, Lennart, Witt, Henning, Noutsias, Michael, Fechner, Henry, Schultheiss, Heinz-Peter, Poller, Wolfgang
Format: Article
Language:English
Subjects:
Adipocytes
Adiponectin
Adiponectin - metabolism
Adiponectin receptors
Adult
Aged
AKT protein
Animals
Apoptosis
Biological and medical sciences
Biopsy
Cardiac muscle
Cardiology
Cardiology. Vascular system
Cardiomyocytes
Cardiomyopathy
Cardiomyopathy, Dilated - metabolism
Cardiomyopathy, Dilated - pathology
Cardiovascular disease
Cardiovascular diseases
Cell survival
Cells, Cultured
Congestive heart failure
Coronary vessels
Cytokines
Diabetes
Dilated cardiomyopathy
Down-Regulation - physiology
Female
Heart
Heart failure
Heart Failure - etiology
Heart failure, cardiogenic pulmonary edema, cardiac enlargement
Humans
Kinases
Male
Medical sciences
Middle Aged
Mortality
mRNA
Myocarditis. Cardiomyopathies
Myocardium - metabolism
Myocardium - pathology
Myocytes
Neonates
Oligonucleotide Array Sequence Analysis
Oligonucleotides
Pathogenesis
Pathology
Patients
Phosphorylation
Proteins
Rats
Receptors, Adiponectin - metabolism
RNA, Messenger - metabolism
Serum levels
Signal Transduction
Therapeutic applications
Therapeutic targets
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-α
Vein & artery diseases
Ventricle
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Summary:Aims Despite recent advances in medical therapy, heart failure remains a leading cause for cardiovascular mortality, and its complex pathogenesis is incompletely understood. This study was performed to identify possible new therapeutic targets in dilated cardiomyopathy (DCM). Methods and results Oligonucleotide microarray analysis was performed on endomyocardial biopsies (EMBs) from patients with early DCM (LVEDD ≥ 55 mm, LVEF ≤ 55%, n = 5) and control subjects (LVEDD < 55 mm, LVEF > 60%, no cardiac pathology, n = 4). Adiponectin, an adipocytokine involved in cellular metabolism, survival, and immunmodulation, was six-fold downregulated in DCM patients. Microarray data for adiponectin were confirmed by TaqMan-PCR (9.2-fold downregulation, control n= 9 vs. DCM n= 9, respectively, P < 0.05). Immunohistological analysis of EMBs showed significant downregulation of cardiac adiponectin protein expression independent of serum adiponectin (P = 0.36, ns) or serum TNFα concentrations (P = 0.46, ns). Neither the adiponectin receptor 1 (adipo-R1) nor adipo-R2 was deregulated in early DCM. Adiponectin mRNA and protein downregulation were confirmed in explanted hearts of patients with advanced DCM (LVEF < 25%, n= 8). In vitro, adiponectin incubation of neonatal rat ventricular myocytes led to activation of the pro-survival kinase PKB/Akt, increased eNOS-phosphorylation, and prevented stress-induced apoptosis of cardiomyocytes in an Akt-dependent manner. Moreover, inhibition of adiponectin secretion was accompanied by an increase in the expression of the cytokine and its receptors. Conclusion These data indicate the existence of a local cardiac adiponectin system regulated independent of adiponectin and TNFα serum levels and its disturbance in cardiac pathology. The study suggests a role for adiponectin in the pathogenesis of DCM and implicates the adipocytokine as a possible future therapeutic target in DCM.
ISSN:0195-668X
1522-9645
DOI:10.1093/eurheartj/ehn136