Abstract 12527: Adiponectin Protects Against Doxorubicin-induced Cardiomyopathy Through An Akt Dependent Mechanism
Background: Although accumulating evidence suggests that an adipocyte-derived plasma protein adiponectin protects against the development of various heart disorders, its role in doxorubicin (DOX)-induced cardiomyopathy has not been examined previously. Here, we investigated the effects of adiponectin on DOX-induced cardiotoxicity and assessed its potential mechanism.
Method: DOX (20mg/kg) or saline as control was intraperitoneally injected into abdomen of adiponectin-knockout (APN-KO) and wild-type (WT) mice. Left ventricular (LV) function was assessed by echocardiography. Myocyte apoptotic activity was determined by TUNEL-staining. Neonatal rat cardiomyocytes were cultured in the presence or absence of recombinant adiponectin followed by treatment with DOX.
Result: APN-KO mice exhibited increased mortality and exacerbated LV contractile dysfunction compared with WT mice at 5 days after DOX injection. APN-KO mice also showed increased apoptotic activity and diminished Akt signaling in the failing myocardium. Systemic delivery of adenoviral vector expressing adiponectin reversed the DOX-induced reduction in LV function in APN-KO mice. In cultured cardiomyocytes, adiponectin stimulated Akt phosphorylation and inhibited DOX-stimulated apoptosis. Phosphatidylinositol 3-kinase inhibitor, LY294002 reversed the inhibitory effects of adiponectin on myocyte apoptosis, suggesting that these actions were mediated via the PI3k-Akt pathway. Calreticulin was detected on the surface of cardiac myocytes, and excess amount of adiponectin reduced the binding of anti-calreticulin antibody to cardiac myocytes by flow cytometric analysis. Adiponectin-mediated increase in Akt activation and survival in cardiomyocytes was diminished by siRNA-mediated knockdown of calreticulin.
Conclusion: Adiponectin protects against DOX-induced cardiac injury by promoting Akt-dependent myocyte survival, which is mediated through an adiponectin receptor calreticulin.
- © 2010 by American Heart Association, Inc.