Ginkgolide A targets forkhead box <scp>O1</scp> to protect against <scp>lipopolysaccharide</scp>‐induced septic cardiomyopathy
Luyang Wang, Yunxi Zhao, Zhenyang Su, Kun Zhao, Peng Li, Tianhua Xu
Abstract
Ginkgolide A (GA), a main terpenoid extracted from Ginkgo biloba, possesses biological activities such as anti-inflammatory, anti-tumor, and liver protection. However, the inhibitory effects of GA on septic cardiomyopathy remain unclear. This study aimed to explore the effects and mechanisms of GA in countering sepsis-induced cardiac dysfunction and injury. In lipopolysaccharide (LPS)-induced mouse model, GA alleviated mitochondrial injury and cardiac dysfunction. GA also significantly reduced the production of inflammatory and apoptotic cells, the release of inflammatory indicators, and the expression of oxidative stress-associated and apoptosis-associated markers, but increased the expression of pivotal antioxidant enzymes in hearts from LPS group. These results were consistent with those of in vitro experiments based on H9C2 cells. Database analysis and molecular docking suggested that FoxO1 was targeted by GA, as shown by stable hydrogen bonds formed between GA with SER-39 and ASN-29 of FoxO1. GA reversed LPS-induced downregulation of nucleus FoxO1 and upregulation of p-FoxO1 in H9C2 cells. FoxO1 knockdown abolished the protective properties of GA in vitro. KLF15, TXN2, NOTCH1, and XBP1, as the downstream genes of FoxO1, also exerted protective effects. We concluded that GA could alleviate LPS-induced septic cardiomyopathy via binding to FoxO1 to attenuate cardiomyocyte inflammation, oxidative stress, and apoptosis.