Abstract P184: Novel Model Of Ionizing Radiation-induced Mouse Coronary Arteriosclerosis, Which Was Attenuated By Precise Time Treatment Of Poly (adp-ribose) Polymerase (parp) Inhibitor

Abstract

Background: It is well known that radiation therapy (RT) induces coronary artery disease (CAD). However, since we don’t have an adequate mouse model to evaluate CAD after RT, it has been difficult to perform pre-clinical study to detect the effective treatment. The inhibition of PARPs can prevent apoptosis and inflammation. Although PARP inhibitors have already been used as anti-tumor agents, their long-term use in CAD is not recommended because the inhibition of DNA damage response can cause DNA instability and eventually cancer. In this study, we restricted the use of PARP inhibitors to the time of IR exposure only and detected IR-induced atherosclerosis (AS). Methods and Results: Marino et al. reported that thoracic aortic constriction (TAC) can exacerbate coronary artery stenosis and myocardial infarction in ApoE -/- mice. We tested this model in LDLR -/- mice that were fed a high fat (HFD) with or without IR (3, 5, and 10 Gy). We observed cardiac hypertrophy and dose-dependent reduction of fractional shortening (FS) after 4-5 weeks of TAC (FS%, 33.74 ± 7.35 (Non-IR, n=9), 26.59 ± 9.19 (3Gy, n=6), 28.49 ± 2.49 (5Gy, n=5), 22.62 ± 6.16 (10Gy, n=6), mean ± SD, p <0.05). Most importantly, we observed localized cardiac dysfunction and infarct only in mice exposed to 10 Gy (n = 2 out of 6), detected by transmural strain analysis with echocardiography. Next, the whole heart was sectioned, with sets of 11 consecutive sections of 5 μm collected every 450 μm interval. We also found the diffuse increase of vascular wall thickness at left anterior descending coronary artery in mice exposed to IR. We fed a HFD on LDLR -/- mice with Olaparib (10 mg/kg/day) or vehicle one day before & after, and the day of IR (5 Gy twice, total 6 days only), then performed TAC. The reduction of FS induced by IR (10 Gy) was significantly improved by the precise time treatment of Olaparib against IR. Conclusion: These data suggested the usefulness of TAC-induced coronary AS mouse model to develop medical countermeasures against RT-induced CAD as pre-clinical study.