European heart journal, 2008-05, Vol.29 (9), p.1168-1180
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.
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.
Cardiology. Vascular system ; Heart ; Biological and medical sciences ; Myocarditis. Cardiomyopathies ; Medical sciences ; Heart failure, cardiogenic pulmonary edema, cardiac enlargement ; Tumor Necrosis Factor-alpha - metabolism ; Cardiomyopathy, Dilated - pathology ; Oligonucleotide Array Sequence Analysis ; Signal Transduction ; Humans ; Middle Aged ; Cells, Cultured ; Rats ; Receptors, Adiponectin - metabolism ; Male ; Myocardium - pathology ; RNA, Messenger - metabolism ; Cardiomyopathy, Dilated - metabolism ; Down-Regulation - physiology ; Animals ; Myocardium - metabolism ; Adiponectin - metabolism ; Adult ; Female ; Aged ; Heart Failure - etiology ; Index Medicus
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