Abstract P2032: Wnt5a Mediates Doxorubicin-induced Cardiomyopathy Through Induction Of Senescence

Abstract

Heart failure and cancer are major causes of death in the United States. Doxorubicin (DOX) is a commonly used chemotherapeutic agent. However, its clinical use is restricted due to cardiotoxicity, which can cause cardiomyopathy as well as heart failure. Senescence is defined by irreversible cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP). Elimination of senescent cells improves cardiac dysfunction, suggesting that senescent cardiomyocytes (CMs) contribute to impaired heart function. Although DOX-induced senescence has been shown to occur in CMs, little is known about the mechanisms mediating DOX-induced cardiomyopathy. Wnt5a, one of the most studied non-canonical Wnt ligands, has emerged as an important player in cardiac diseases. mRNA expression of Wnt5a is upregulated in induced pluripotent stem cells (iPSC)-derived CMs from patients with end-stage heart failure induced by DOX chemotherapy. However, the role of Wnt5a in mediating the progression of DOX-induced cardiomyopathy remains elusive. We found that Wnt5a protein expression is markedly increased in mouse hearts with DOX-induced cardiomyopathy. Upregulation of Wnt5a following DOX treatment was also observed in neonatal rat CMs (NRCMs), and the degree of upregulation was more prominent in CMs than in non-CMs. We tested whether Wnt5a induces the senescent phenotype in NRCMs. Wnt5a not only induced an increase in p16 protein levels but also increased the number of γH2AX foci per cell and SA-β-gal activity in NRCMs. Wnt5a knockdown markedly reduced DOX-induced increases in p16 protein levels in NRCMs. These results suggest that DOX may induce cardiomyopathy through Wnt5a-mediated induction of CM senescence. Wnt5a may be a novel therapeutic target for the prevention of DOX-induced cardiac dysfunction.