Abstract:

Objective To discuss the protective effectof follistatin-like 1 （FSTL1） on doxorubicin （DOX）-induced acute myocardial injury of the mice，and to clarify its related mechanism. Methods A total of 80 C57BL/6J mice were used to establish the acute myocardial injury models by intraperitoneal injection of DOX for one time.The mice were divided into 5 groups （n=8） according to the different doses （0，5，10，15， and 20 mg·kg^－1） of DOX，and didvided into 5 groups（n=8） according to the different intervention time（0，0.5，1.0，2.0，and 3.0 d）.The other 32 mice were randonly divided into normal saline group，FSTL1 group，DOX group， and DOX-FSTL1 group.The echocardiographic and hemodynamic indexes of the mice in various groups were detected；enzyme-linked immunosorbent assay（ELISA） method was used to detect the levels of tumor necrosis factor-α（TNF-α），N-terminal pro-brain natriuretic peptide（NT-proBNP） and cardiae troponin-T（cTn-T） in serum of the mice in various groups；the activities of superoxide dismutase （SOD）， the levels of malondialdehyde （MDA）， 4-hydroxynonenal （4-HNE） and 15-F_2t isoprostane in myocardium tissue of the mice in various groups were detected by oxidative stress kit；the expression levels of FSTL1 mRNA in myocardium tissue of the mice in various groups were detected by real-time fluorescence quantitative PCR （RT-qPCR） method； the expression levels of nuclear factor E2 related factor 2 （Nrf2） and FSTL1 proteins in myocardium tissue of the mice in various groups were detected by Western blotting method. Results Compared with normal saline group， the left ventricular ejection fraction（LVEF），left ventricular fraction shortening（ LVFS）， left ventricular systolic pressure（LVSP）， maximum rise rate of left ventricular pressure（+dP/dt_max），and maximum drop rate of left ventricular pressure（－dp /dt_max） of the mice in DOX group and DOX+FSTL1 group were significantly decreased（P<0.05）， and the heart rate（HR），left ventricular end-diastolic volume（LVEDV），and left ventricular diastolic pressure were increased （P<0.05）； compared with DOX group， the LVEF，+dP/dt_max， and －dp /dt_max of the mice in DOX+FSTL1 group were significantly increased（P<0.05），and the LVEDV was significantly decreased （P<0.05）. Compared with normal saline group， the serum levels of TNF-α， NT-proBNP and cTn-T in serum of the mice in DOX group and DOX+FSTL1 group were significantly increased （P<0.05）； compared with DOX group， the serum levels of NT-proBNP and cTn-T in serum of the mice in DOX+FSTL1 group were significantly decreased （P<0.05）. Compared with normal saline group， the activity of SOD in myocardium tissue of the mice in DOX group was significantly decreased （P<0.05）， and the levels of MDA， 4-HNE， and 15-F_2t-isoprostane were significantly increased （P<0.05），the level of 15-F_2t-isoprostane in serum of the mice in DOX+FSTL1 group was increased （P<0.05）； compared with DOX group， the SOD activity in myocardium tissue of the mice in DOX+FSTL1 group was increased （P<0.05）， and the levels of MDA， 4-HNE， and 15-F_2t-isoprostane were decreased （P<0.05）.Compared with 0 mg·kg^－1 DOX group， the levels of FSTL1 mRNA in myocardium tissue of the mice in the other groups were significantly decreased with the increasing of the doxorubicin dose （P<0.05）. Compared with DOX 0 d group， the levels of FSTL1 mRNA in myocardium tissue of the mice in the other groups were significantly decreased with the prolongation of the doxorubicin intervention time （P<0.05）. Compared with normal saline group，the expresison levels of FSTL1 and Nrf2 proteins in myocardium tissue of the mice in DOX group was decreased（P<0.05）；compared with DOX group， the expression levels of FSTL1 and Nrf2 proteins in myocardium tissue of the mice in DOX+FSTL1 group were increased （P<0.05）. Conclusion FSTL1 can alleviate the DOX-induced acute myocardial injury and improve the cardiac function by regulating the oxidative stress， and its mechanism may be reated to up-regulating the Nrf2 expression.

Key words: Follistatin-like 1, Doxorubicin, Myocardial injury, Cardiotoxicity, Oxidative stress