Matricellular protein CCN1 mediates doxorubicin-induced cardiomyopathy in mice

Pei-Ling Hsu, Fan-E Mo
Oncotarget 2016 June 14, 7 (24): 36698-36710
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 (Ccn1dm/dm) expressing an a6β1-binding defective CCN1 mutant were treated with a single dose of DOX (15 mg/kg; i.p.). Compared with wild-type mice, Ccn1dm/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 a6β1 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/a6β1 engagement abolishes DOX-associated cardiomyopathy in mice.

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