Abstract 751: The Inhibition of PARP Provides Greatercardioprotection in Mice With Heart Failure

The most cause of death in Japan is cancer and the second is heart disease. It is expected that the number of patients with both diseases will continue to increase in the increasingly aging society. Cardiotoxicity by anticancer agents has been recognized for a long time, for example alkylating agents, antimetabolites, proteasome inhibitors, and anthracycline anticancer agents. As cancer patients and heart failure patients increase, the number of patients suffering both diseases at the same time will naturally increase. In recent years, many new anticancer drugs have been developed and are on the market in succession, and the research on cardiotoxicity in each drug has not kept up. In 2017, from our group, there was a report that inflammation was caused by an increase in cardiomyocyte single strand breaks in pressure-overload heart failure model mice, and that inflammation contributes to declining cardiac function . DNA repair related protein PARP1 plays an important role in the repair mechanism of SSBs. PARP inhibitor disturbs its mechanism and exerts antitumor effect by causing tumor cells to become apoptosis. Therefore, we hypothesize that orally administered PARP inhibitors in heart failure patients will inhibit DNA repair by PARP, thus exacerbate inflammation and impair cardiac function more. To examine this hypothesis, we administered a representative PARP inhibitor, olaparib to pressure-overload heart failure model mice. Surprisingly, the cardiac function was improved in the olaparib administrated group. PARP is known to recruit DNA repair related proteins through synthesis of PAR (Poly-ADP-Ribose) on the DNA damage sites. In recent reports, several studies have shown that the accumulation of PAR would be involved in the worsening of the disease state in cerebellar degenerative ataxia and Parkinson's disease. In our immunostaining study of PAR using the heart tissue specimens from 58 patients with dilated cardiomyopathy, PAR was stained much more in patients with poor outcomes. I believe that PARP inhibitors may have a cardioprotective effect by preventing the accumulation of PAR, and we are now conducting further analyzes.