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 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. CONCLUSION 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.

[1]  F. Van de Werf,et al.  Cardiomyocyte-Specific Overexpression of Nitric Oxide Synthase 3 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction , 2004, Circulation research.

[2]  Y. Taniyama,et al.  Elevated myocardial Akt signaling ameliorates doxorubicin-induced congestive heart failure and promotes heart growth. , 2002, Journal of molecular and cellular cardiology.

[3]  Philippe Froguel,et al.  Cloning of adiponectin receptors that mediate antidiabetic metabolic effects , 2003, Nature.

[4]  M. Picard,et al.  Pressure overload-induced LV hypertrophy and dysfunction in mice are exacerbated by congenital NOS3 deficiency. , 2004, American journal of physiology. Heart and circulatory physiology.

[5]  Lei Wang,et al.  Regulation of cardiomyocyte apoptotic signaling by insulin-like growth factor I. , 1998, Circulation research.

[6]  T. Suganami,et al.  A Paracrine Loop Between Adipocytes and Macrophages Aggravates Inflammatory Changes: Role of Free Fatty Acids and Tumor Necrosis Factor α , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[7]  J. Engel,et al.  Structure-Function Studies of the Adipocyte-secreted Hormone Acrp30/Adiponectin , 2003, The Journal of Biological Chemistry.

[8]  S. Kihara,et al.  Adiponectin Stimulates Angiogenesis in Response to Tissue Ischemia through Stimulation of AMP-activated Protein Kinase Signaling* , 2004, Journal of Biological Chemistry.

[9]  Y. Nakano,et al.  Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. , 1996, Journal of biochemistry.

[10]  H. Lodish,et al.  Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  H. Fechner,et al.  Genomic expression profiling of human inflammatory cardiomyopathy (DCMi) suggests novel therapeutic targets , 2006, Journal of Molecular Medicine.

[12]  Jan Frystyk,et al.  Plasma Adiponectin, Body Mass Index, and Mortality in Patients With Chronic Heart Failure , 2005, Circulation.

[13]  T. Kadowaki,et al.  Adiponectin and adiponectin receptors. , 2005, Endocrine reviews.

[14]  S. Anker,et al.  Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure. , 1997, Journal of the American College of Cardiology.

[15]  A. Shah,et al.  Increased neuronal nitric oxide synthase-derived NO production in the failing human heart , 2004, The Lancet.

[16]  H. Tilg,et al.  Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice. , 2006, Journal of hepatology.

[17]  S. Brichard,et al.  Induction of adiponectin in skeletal muscle by inflammatory cytokines: in vivo and in vitro studies. , 2004, Endocrinology.

[18]  Herbert Tilg,et al.  Adipocytokines: mediators linking adipose tissue, inflammation and immunity , 2006, Nature Reviews Immunology.

[19]  T. Funahashi,et al.  cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). , 1996, Biochemical and biophysical research communications.

[20]  D. Hardie,et al.  AMP-activated protein kinase: the guardian of cardiac energy status. , 2004, The Journal of clinical investigation.

[21]  S. Uchida,et al.  Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature Medicine.

[22]  R. Piñeiro,et al.  Adiponectin is synthesized and secreted by human and murine cardiomyocytes , 2005, FEBS letters.

[23]  S. Kihara,et al.  Adiponectin protects against the development of systolic dysfunction following myocardial infarction. , 2007, Journal of molecular and cellular cardiology.

[24]  A. M. Lefer,et al.  Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  R. Kitsis,et al.  Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. , 2000, Circulation.

[26]  Anne L. Taylor.  The African American Heart Failure Trial: a clinical trial update. , 2005, The American journal of cardiology.

[27]  T. Kanda,et al.  Reduced-energy diet improves survival of obese KKAy mice with viral myocarditis: induction of cardiac adiponectin expression. , 2007, International journal of cardiology.

[28]  R. Hajjar,et al.  Adenoviral gene transfer of activated phosphatidylinositol 3'-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. , 1999, Circulation.

[29]  T Nakamura,et al.  Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. , 1999, Biochemical and biophysical research communications.

[30]  S. Kihara,et al.  Adiponectin-mediated modulation of hypertrophic signals in the heart , 2004, Nature Medicine.

[31]  K. Mani,et al.  Death begets failure in the heart. , 2005, The Journal of clinical investigation.

[32]  T. Funahashi,et al.  Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism. , 2005, Cardiovascular research.

[33]  Philipp E. Scherer,et al.  A Novel Serum Protein Similar to C1q, Produced Exclusively in Adipocytes (*) , 1995, The Journal of Biological Chemistry.

[34]  H. Sumino,et al.  Adiponectin Replacement Therapy Attenuates Myocardial Damage in Leptin-deficient Mice with Viral Myocarditis , 2005, The Journal of international medical research.

[35]  David M Maahs,et al.  Low Plasma Adiponectin Levels Predict Progression of Coronary Artery Calcification , 2005, Circulation.

[36]  R. Vetter,et al.  Influence of different culture conditions on sarcoplasmic reticular calcium transport in isolated neonatal rat cardiomyocytes , 1998, Molecular and Cellular Biochemistry.

[37]  M. Birnbaum,et al.  AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. , 2004, The Journal of clinical investigation.

[38]  I. Shiojima,et al.  Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. , 2005, The Journal of clinical investigation.

[39]  S. Kihara,et al.  Adiponectin Stimulates Angiogenesis by Promoting Cross-talk between AMP-activated Protein Kinase and Akt Signaling in Endothelial Cells* , 2004, Journal of Biological Chemistry.

[40]  K. Walsh,et al.  Targeting adiponectin for cardioprotection , 2006, Expert opinion on therapeutic targets.

[41]  NoriyukiOuchi,et al.  Association of Hypoadiponectinemia With Coronary Artery Disease in Men , 2003 .

[42]  Morihiro Matsuda,et al.  Increased oxidative stress in obesity and its impact on metabolic syndrome. , 2004, The Journal of clinical investigation.

[43]  藤岡 大佑.  Role of adiponectin receptors in endothelin-induced cellular hypertrophy in cultured cardiomyocytes and their expression in infarcted heart , 2007 .

[44]  S. Kihara,et al.  Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2–dependent mechanisms , 2005, Nature Medicine.

[45]  S. Kihara,et al.  Adiponectin accumulates in myocardial tissue that has been damaged by ischemia-reperfusion injury via leakage from the vascular compartment. , 2007, Cardiovascular research.

[46]  Qinglin Yang,et al.  Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor gamma. , 2007, Journal of molecular and cellular cardiology.

[47]  T. Funahashi,et al.  Decreased plasma adiponectin concentration in patients with essential hypertension. , 2003, American journal of hypertension.

[48]  S. Kihara,et al.  Obesity, adiponectin and vascular inflammatory disease , 2003, Current opinion in lipidology.

[49]  R. Kandolf,et al.  High Prevalence of Viral Genomes and Multiple Viral Infections in the Myocardium of Adults With “Idiopathic” Left Ventricular Dysfunction , 2005, Circulation.

[50]  P. Ponikowski,et al.  Wasting as independent risk factor for mortality in chronic heart failure , 1997, The Lancet.

[51]  T. Ogihara,et al.  Hypoadiponectinemia Is an Independent Risk Factor for Hypertension , 2004, Hypertension.

[52]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[53]  B. Spiegelman,et al.  AdipoQ Is a Novel Adipose-specific Gene Dysregulated in Obesity (*) , 1996, The Journal of Biological Chemistry.

[54]  H. Tilg,et al.  Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. , 2004, Biochemical and biophysical research communications.

[55]  NoriyukiOuchi,et al.  Novel Modulator for Endothelial Adhesion Molecules , 1999 .