Semaglutide Pretreatment Induces Cardiac Autophagy to Reduce Myocardial Injury in Septic Mice.

BACKGROUND: Sepsis-induced myocardial dysfunction (SIMD) confers substantial morbidity and mortality. Semaglutide treatment has demonstrated efficacy in ameliorating sepsis-related organ damage via attenuation of inflammation, oxidative stress, and apoptotic cell death. In this study, we constructed a mouse SIMD model using cecal ligation and puncture (CLP) to explore whether semaglutide preconditioning can modulate autophagy levels and attenuate myocardial injury. METHODS: C57BL/6 mice were randomly divided into six groups: sham, CLP (including CLP-6 h, CLP-12 h and CLP-24 h subgroups), semaglutide, and semaglutide+Compound-C, with five mice in each group. The latter two groups were given daily intraperitoneal injections of semaglutide for 14 days. The semaglutide+Compound-C group was given the autophagy inhibitor Compound-C intraperitoneally 1-hour before CLP surgery. After the last injection of semaglutide, SIMD mouse models were constructed by CLP surgery, while the sham group underwent a sham operation. All mice were sacrificed after surgery, and blood and myocardial specimens were collected. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of inflammatory factors and myocardial injury markers in the serum, while quantitative real-time polymerase chain reaction (qRT-PCR) and western blot was used to detect the expression of autophagic markers [microtubule-associated protein 1A/1B-light chain 3B (LC3B), Beclin-1, p62] and AMP-activated protein kinase (AMPK) in myocardial tissue. Hematoxylin and eosin (H&E) staining was used to observe pathological changes in myocardial tissue. RESULTS: The myocardial fibers in the sham group were normal, while those in the CLP group showed disordered arrangement, interstitial edema, and a large number of infiltrating inflammatory cells. A few vacuolar changes were observed locally in the semaglutide group, and more vacuolar changes were observed in the semaglutide+Compound-C group. Autophagy was inhibited in the CLP group mice. Compared with the CLP group, the semaglutide group showed a decreased levels of inflammatory factors (tumor necrosis factor-α, interleukin-1β) and myocardial injury markers (creatine kinase isoenzyme, cardiac troponin T) in the serum, a reduced expression of autophgic substrate p62, and an increased expression of LC3II (the lipidated form of LC3I)/LC3I (microtubule-associated protein 1A/1B-light chain 3), Beclin-1, and p-AMPK (phosphorylated AMP-activated protein kinase)/AMPK in the injured myocardial tissues of mice ( < 0.05). And the protective effects of semaglutide against SIMD were partially reversed by the treatment of AMPK inhibitor Compound-C ( < 0.05). CONCLUSIONS: Taken together, these data indicate that semaglutide provides protection against CLP-triggered myocardial inflammation and injury, potentially by reactivating myocardial autophagy pathways via activation of AMPK signaling. Further mechanistic studies are needed to definitively elucidate the functional significance of AMPK signaling in mediating the beneficial cardiac effects of semaglutide during sepsis.