Matricellular protein CCN1 mediates doxorubicin-induced cardiomyopathy in mice

// Pei-Ling Hsu 1, 2 , Fan-E Mo 1, 2 1 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan 2 Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan Correspondence to: Fan-E Mo, e-mail: femo@mail.ncku.edu.tw Keywords: CCN1, doxorubicin, cardiotoxicity, integrins, XIAP Received: November 09, 2015      Accepted: April 23, 2016      Published: May 4, 2016 ABSTRACT Doxorubicin (DOX) is an effective chemotherapeutic agent however its clinical use is limited by its cumulative cardiotoxicity. Matricellular protein CCN1 mediates work-overload-induced cardiac injury. We aimed to assess the role of CCN1 in DOX-associated cardiomyopathy. Here we discovered CCN1 expression in the myocardium 1 day after DOX treatment (15 mg/kg; i.p.) in mice. Whereas CCN1 synergizes with Fas ligand (FasL) to induce cardiomyocyte apoptosis, we found that FasL was also induced by DOX in the heart. To assess the function of CCN1 in vivo , knockin mice ( Ccn1 dm/ dm ) expressing an a 6 β 1 -binding defective CCN1 mutant were treated with a single dose of DOX (15 mg/kg; i.p.). Compared with wild-type mice, Ccn1 dm/dm mice were resistant to DOX-induced cardiac injury and dysfunction 14 days after injection. Using rat cardiomyoblast H9c2 cells, we demonstrated that DOX induced reactive oxygen species accumulation to upregulate CCN1 and FasL expression. CCN1 mediated DOX cardiotoxicity by engaging integrin a 6 β 1 to promote p38 mitogen-activated protein kinase activation and the release of mitochondrial Smac and HtrA2 to cytosol, thereby counteracting the inhibition of XIAP and facilitating apoptosis. In summary, CCN1 critically mediates DOX-induced cardiotoxicity. Disrupting CCN1/a 6 β 1 engagement abolishes DOX-associated cardiomyopathy in mice.