Isopropyl 3-(3,4-dihydroxyphenyl) 2-hydroxypropanoate protects septic myocardial injury via regulating GAS6/Axl-AMPK signaling pathway.

ABSTRACT

In a previous study, we used metabolomic techniques to identify a new metabolite of Danshen Dripping Pills called isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate (IDHP), which has potential as a drug candidate for cardiovascular diseases. This study aimed to explore the protective effects of IDHP against septic myocardial injury, as well as its molecular mechanism. Wild type or GAS6 knockout mice injured by cecal ligation and puncture (CLP) were used to observe the effect of IDHP. Here, we found that a specific concentration of IDHP (60 mg/kg) significantly increased the survival rate of septic mice to about 75 % at 72 h post CLP, and showed improvements in sepsis score, blood biochemistry parameters, cardiac function, and myocardial tissue damage. Furthermore, IDHP inhibited myocardial oxidative stress, inflammatory response, apoptosis, and mitochondrial dysfunction. Molecularly, we discovered that IDHP treatment reversed the CLP-induced downregulation of GAS6, Axl, and p-AMPK/AMPK expression. In addition, GAS6 knockout reversed the positive effect of IDHP in septic mice, indicated by more severe myocardial tissue damage, oxidative stress, inflammatory response, and mitochondrial dysfunction. GAS6 knockout also resulted in decreased levels of GAS6, Axl, and p-AMPK/AMPK. Taken together, our study provides evidence that IDHP has significant cardioprotective effects against sepsis by regulating the GAS6/Axl-AMPK signaling pathway. This finding has important therapeutic potential for treating sepsis.