title: Adiponectin ameliorates doxorubicin-induced cardiotoxicity through Akt protein-dependent mechanism.
abstract: Accumulating evidence shows that obesity is associated with doxorubicin cardiac toxicity in the heart, but the molecular mechanisms that contribute to this pathological response are not understood. Adiponectin is an adipose-derived, cardioprotective factor that is down-regulated in obesity. Here, we investigated the effect of adiponectin on doxorubicin (DOX)-induced cardiotoxicity and assessed the mechanisms of this effect. A single dose of DOX was intraperitoneally injected into the abdomen of adiponectin knock-out (APN-KO) and wild-type (WT) mice. APN-KO mice had increased mortality and exacerbated contractile dysfunction of left ventricle compared with WT mice. APN-KO mice also showed increased apoptotic activity and diminished Akt signaling in the failing myocardium. Systemic delivery of adenoviral vector expressing adiponectin improved left ventricle dysfunction and myocardial apoptosis following DOX injection in WT and APN-KO mice but not in Akt1 heterozygous KO mice. In cultured rat neonatal cardiomyocytes, adiponectin stimulated Akt phosphorylation and inhibited DOX-stimulated apoptosis. Treatment with sphingosine kinase-1 inhibitor or sphingosine 1-phosphate receptor antagonist diminished adiponectin-induced Akt phosphorylation and reversed the inhibitory effects of adiponectin on myocyte apoptosis. Pretreatment with anti-calreticulin antibody reduced the binding of adiponectin to cardiac myocytes and blocked the adiponectin-stimulated increase in Akt activation and survival in cardiomyocytes. Interference of the LRP1/calreticulin co-receptor system by siRNA or blocking antibodies diminished the stimulatory actions of adiponectin on Akt activation and myocyte survival. These data show that adiponectin protects against DOX-induced cardiotoxicity by its ability to promote Akt signaling.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Sonomi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.forename: Koji
authors.initials: K
authors.lastname: Ohashi
authors.forename: Taiki
authors.initials: T
authors.lastname: Ohashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Daida
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
mesh_terms: D052242:Adiponectin / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D065095:Calcineurin Inhibitors; D054715:Cardiotoxins / Q000009:adverse effects* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D009206:Myocardium / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D000903:Antibiotics, Antineoplastic; D057134:Antibodies, Neutralizing; D065095:Calcineurin Inhibitors; D054715:Cardiotoxins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D049349:Receptors, Lysosphingolipid; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D019703:Calcineurin