Inhibiting PPP1R3G/PP1γ activity to prevent oxidative stress- and ischemia-induced cardiac injury

Necroptosis and apoptosis are two distinct cell death pathways that play pivotal functions in cardiac pathological conditions. RIPK1 is a crucial player in these two types of cell death, and its kinase activity is under complex regulation. Through a CRISPR whole genome knockout screen, we discovered that PPP1R3G, a regulatory subunit of protein phosphatase1(PP1), is required for RIPK1 activation and subsequent cell death. This project aims to define the in vivo function of PPP1R3G in cardiac injury and develop inhibitors targeting at PPP1R3G/PP1γ to prevent the injury. The results showed that Ppp1r3g knockout mice are protected from doxorubicin-induced cardiac injury and exhibit less apoptosis and necroptosis in the hearts. In MI models, Ppp1r3g-/- mice have a lower rate of heart rupture in the acute phase. In collaboration with Dr. Jianfeng Cai’s group in the Chemistry department, a series of chemical inhibitors targeting at PPP1R3G/PP1γ were developed. Some of them show powerful efficacy in inhibiting cell death in vitro and preventing tumor necrosis factorα(TNFα)-induced lethal sepsis in vivo. Their effect on cardiac injury will be examined next.