LAUSR

Background and purpose Olaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) have recently been approved for human use for oncological indications. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effect of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in-vivo model of cardiac transplantation. Experimental approach H9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10μM) were challenged with either hydrogen-peroxide (H2O2) or with glucose-oxidase (GOx, which generates H2O2 in the tissue culture medium). Cell viability assays (MTT, lactate dehydrogenase) and Western blotting for PARP and its product, PAR was conducted. In-vivo studies of heterotopic heart transplantation were performed in an isogenic Lewis to Lewis rat strain; recipients were treated either with vehicle or olaparib (10mg/kg). Left-ventricular function of the transplanted heart was monitored via a Millar-catheter-system. Multiple gene expression in the transplanted hearts was measured by qPCR. Key results Olaparib blocked autoPARylation of PARP1 and attenuated the H2O2-induced rapid-onset H9c2 cell-death, but did not affect cell-death in response to chronic, prolonged oxidative stress induced by GOx. In rats, after transplantation, left-ventricular systolic and diastolic function were significantly improved by olaparib. Olaparib was also associated with reduced gene expression in the transplanted hearts for c-jun, caspase-12, catalase, and NADPH-oxidase-2. Conclusions and Implications Olaparib reduces oxidative stress-induced myocyte injury in-vitro and improves cardiac function in a transplantation model in-vivo. These findings raise the possibility of repurposing of this clinically approved oncology drug to be used in heart transplantation.