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.

Adipocytokines in Cardiovascular and Metabolic Diseases

“…Conversely, overexpression of adiponectin improves left ventricular hypertrophy, diastolic dysfunction and myocardial oxidative stress in response to aldosterone infusion 36) . We have also demonstrated that adiponectin prevents doxorubicin-induced cardiotoxicity through its ability to stimulate myocyte survival 37) . Overall, adiponectin acts as an adipocytokine that protects against the development of various heart diseases.…”

Concomitant low-dose doxorubicin treatment and exercise

“…Although exercise training has previously been shown to increase Akt phosphorylation (3), the role of Akt in DOX cardiotoxicity is less clear. While some studies have shown DOX decreases Akt phosphorylation, others have observed elevated Akt activity in vivo (6,11,25). Because many factors influence Akt phosphorylation, it appears the experimental model is very important for interpretation of Akt activity.…”

Obesity As a Risk Factor for Anthracyclines and Trastuzumab Cardiotoxicity in Breast Cancer: A Systematic Review and Meta-Analysis

“…64 Adiponectin-KO mice showed exacerbated left ventricle contractile dysfunction after doxorubicin injection, whereas exogenous adiponectin improved doxorubicin-induced left ventricular dysfunction in wild-type and adiponectin-KO mice. 62 However, no study has yet been performed to elucidate the role of adiponectin on trastuzumab-induced cardiac dysfunction.…”

“…60 Mechanisms by which overweight or obesity is able to promote anthracycline-induced cardiotoxicity may involve adiponectin downregulation. 61,62 The dysregulation of adipocyte-derived hormones, adipocytokines, promotes the development of diverse obesity-linked diseases. 63 Plasma adiponectin levels are decreased in obese patients.…”