Small molecule inhibition of cyclic GMP-AMP synthase ameliorates sepsis-induced cardiac dysfunction in mice

Aims: Cardiac dysfunction is the main cause of multi-organ failure following sepsis within critical care units. The present study aimed to investigate the effects of the small molecule inhibition of Cyclic GMP-AMP Synthase (cGAS), RU.521, on cardiac function in mice with sepsis.

Materials and methods: Sepsis was induced in mice via intraperitoneal lipopolysaccharide (LPS) injection (10 mg/kg, i.p.). Mice subsequently received 5 mg/kg RU.521 within 10 min form LPS injection. The cardiac function, inflammatory factor and oxidative stress of mice were examined for 24 h following LPS injection.

Key findings: RU.521 was indicated to significantly increase the cardiac function of mice with sepsis. In addition, the inflammatory responses, oxidative stress and Apoptosis in hearts of sepsis mice were markedly mitigated by RU.521. Moreover, inhibition of SIRT3 inhibited the protective effects of RU.521 on mice with sepsis.

Significance: The current study indicated that RU.521 alleviated the inflammatory response and alleviated the damage induced by oxidative stress, leading to cardiac protection via increased SIRT3 expression in the hearts of mice with sepsis.