PARP1 mediates the PI3K/AKT signaling pathway through PARylation-dependent to alleviate the myocardial injury caused by Cediranib
J Ma, X Fan, Y Wang, X Ma, C Feng, L Wang, J YuAbstract
Background
Vascular endothelial growth factor receptor inhibitors(VEGFRI), as drugs targeting angiogenesis, are widely used in the treatment of various malignant tumors with remarkable therapeutic effects. However, due to its off-target effect, it may cause cardiovascular side effects, which has also become one of the main causes of death for cancer patients. Cancer therapy-related cardiac dysfunction(CTRCD) is associated with the use of VEGFRI. Poly(ADP-ribose) polymerase 1 (PARP1) is a major factor in cardiovascular disease. Elevated PARP1 expression and poly (ADP-ribose) ylation were observed in cardiac remodeling. The increase in PARP1 activity leads to extreme energy consumption by myocardial cells. Meanwhile, in cardiac injury caused by anti-tumor treatment, the application of PARP inhibitors can improve LVEF and CO in model mice. PARP1 can modify and regulate multiple signaling pathways through PARylatyion, and participate in various activities of cells such as proliferation, apoptosis, oxidative stress, and autophagy.
Purpose
This study explored whether the PARP inhibitor Olaparib could improve cardiac insufficiency caused by VEGFRI, and demonstrated that PARP1 could mediate the PI3K/AKT signaling pathway through PARylylation dependence, thereby improving CTRCD
Methods
All mice were randomly divided into the control group, Cediranib group, Cediranib + Olaparib group, and Olaparib group. They were adaptively raised for one week and were respectively given 2ml/kg/day of normal saline, 6mg/kg/d of Cediranib, 6mg/kg/d of Cediranib + 50mg/kg/d of Olaparib. After continuous administration for 35 days, The mice were anesthetized by inhaling 1.0-2.5% isoflurane to collect blood, and the tissues were immediately frozen in liquid nitrogen.
Results
Proteomics detection revealed the PI3K/AKT signaling pathway was significantly altered. Small animal ultrasound indicated that the ejection fraction of mice decreased. HE staining showed that the myocardial tissue was disordered and myocardial cells were damaged. Masson staining showed that collagen fibers in the myocardial interstitium were deposited and myocardial fibrosis occurred. Further Western Blot showed that compared with the control group, the oxidative stress markers SOD1 and OGG1 were significantly increased, and the expression of PARP1 was increased, while the ratios of P-PI3K/PI3K and P-AKT/AKT decreased. Further experiments demonstrated that after treatment with Cediranib combined with the Olaparib, the LVEFof mice did not show a significant decrease. Pathological staining indicated that myocardial damage improved and the degree of fibrosis was reduced, and oxidative stress markers did not show a significant increase. the expression of PARP1 was decreased compared with Cediranib group, while the ratios of P-PI3K/PI3K and P-AKT/AKT increased.
Conclusions
PARP1 mediates the PI3K/AKT signaling pathway through PARylation-dependent to alleviate the myocardial injury.FIG 1