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


RESULTS
Oligonucleotide microarray analysis was performed on endomyocardial biopsies (EMBs) from patients with early DCM (LVEDD > or = 55 mm, LVEF < or = 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 TNFalpha 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.


CONCLUSIONS
These data indicate the existence of a local cardiac adiponectin system regulated independent of adiponectin and TNFalpha 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.
Skurk
Carsten
C
Department of Cardiology and Pneumology, Campus Benjamin Franklin, Charité University Medicine Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. skurkc@yahoo.com
Wittchen
Frank
F
Suckau
Lennart
L
Witt
Henning
H
Noutsias
Michael
M
Fechner
Henry
H
Schultheiss
Heinz-Peter
HP
Poller
Wolfgang
W
D052242:Adiponectin / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006333:Heart Failure / Q000209:etiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D054419:Receptors, Adiponectin / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D052242:Adiponectin; D012333:RNA, Messenger; D054419:Receptors, Adiponectin; D014409:Tumor Necrosis Factor-alpha