OONO^–/MMP2/MMP9 pathway-mediated apoptosis of porcine granulosa cells is associated with DNA damage

Granulosa cells play a crucial role in the development of follicles, and their cell apoptosis in the porcine ovary is a major contributor to follicular atresia. Here, we provide a new mechanism for follicular atresia by describing a crucial mechanism by which peroxynitrite anion (OONO^–) may cause GC death. We discovered that nitric oxide, oxidative stress level, and OONO^– were positively correlated with porcine follicular atresia, which was accompanied by high expression of matrix metalloproteinase 2 (MMP2) and MMP9. We created a model of OONO^–-induced apoptosis in GCs and discovered that OONO^– could boost the expression of MMP2 and MMP9 and increase the expression of pro-apoptotic proteins and DNA damage. Furthermore, by inhibiting the activities of MMP2 and MMP9, we found that SB-3CT (a specific inhibitor for MMP2 and MMP9) alleviated the decrease in cell survival rates and DNA damage caused by OONO^–, which may have been impacted by reducing the cleavage of PARP1 by MMP2 and MMP9. Therefore, our findings imply that OONO^– can cause DNA damage to GCs, participating in mediating the expression of pro-apoptotic proteins and inhibiting DNA repair by preventing the activity of PARP1 through MMP2 and MMP9. These results help explain how OONO^–/MMP2/MMP9 affects porcine follicular atresia and GC apoptosis.

© 2023 Society for Reproduction and Fertility