Metformin pretreatment induces cardiac autophagy to reduce myocardial injury in septic mice
- VernacularTitle:二甲双胍预处理诱导心脏自噬减轻脓毒症小鼠的心肌损伤
- Author:
Yong TIAN
1
,
2
;
Ying ZHOU
;
Yongxiang GU
;
Guohui YANG
Author Information
- Keywords: metformin; autophagy; sepsis; inflammatory response; myocardial injury
- From: Chinese Journal of Tissue Engineering Research 2024;28(28):4469-4476
- CountryChina
- Language:Chinese
- Abstract: BACKGROUND:Sepsis complicated by myocardial injury is characterized by a high mortality.Metformin can prevent sepsis-induced myocardial dysfunction by exerting anti-inflammatory effects,improving oxidative stress,and reducing apoptosis.However,it is unclear whether metformin-induced autophagy plays an important role in the protective effect against sepsis-induced myocardial injury. OBJECTIVE:To explore the effect of metformin pretreatment on myocardial injury in septic mice. METHODS:A total of 40 male Kunming mice were randomly divided into sham operation group,model group,metformin group,and metformin+ 3-methyladenine group,with 10 mice in each group.The latter two groups were intraperitoneally injected with metformin for 14 days at a fixed time every day,and the metformin+3-methyladenine group was intraperitoneally injected with 3-methyladenine 1 hour before modeling.Twenty-four hours after the last injection of metformin,cecal ligation and perforation were used to construct a model of myocardial injury in septic mice.The sham operation group was not ligated and perforated.All mice were sacrificed 24 hours after surgery,and blood and myocardial specimens were collected.The levels of inflammatory factors and myocardial injury markers in serum were detected by ELISA.The mRNA expression of autophagy markers LC3B and p62 in myocardial tissue was detected by RT-qPCR.The protein expression of LC3B,Beclin-1,p62,p-AMPK,and AMPK in myocardial tissue was detected by western blot.The pathological changes in myocardial tissue were detected by hematoxylin-eosin staining. RESULTS AND CONCLUSION:Autophagy was inhibited in septic mice with myocardial injury.Compared with the sham operation group,the levels of serum tumor necrosis factor-α,interleukin-1β,interleukin-6,creatine kinase isoenzyme,and troponin T were increased in the model group(P<0.05),but there was no significant difference in p62,LC3Ⅱ/LC3Ⅰ,and p-AMPK/AMPK between the two groups(P>0.05).Compared with the model group,the levels of tumor necrosis factor-α,interleukin-6,creatine kinase isoenzyme,troponin T,and p62 were decreased in the metformin group(P<0.05),while LC3Ⅱ/LC3Ⅰ,p-AMPK/AMPK and Beclin-1 level were increased(P<0.05).Compared with the metformin group,the levels of tumor necrosis factor-α,interleukin-6,creatine kinase isoenzyme,troponin T,and p62 were increased in the metformin+3-methyladenine group(P<0.05),while LC3Ⅱ/LC3Ⅰ and Beclin-1 level were decreased(P<0.05).Myocardial hematoxylin-eosin staining indicated that myocardial fibers arranged normally in the sham operation group,but disorderedly in the model group,with interstitial edema and a large number of infiltrated inflammatory cells.A small amount of vacuolar changes were observed in the metformin group.The arrangement of myocardial fibers in the metformin+3-methyladenine group was slightly disordered,with more vacuolar changes.To conclude,metformin pretreatment may reduce myocardial injury in septic mice by activating the AMPK signaling pathway and inducing autophagy.
