11β-HSD1 inhibitor alleviates sepsis-induced cardiac dysfunction by regulating macrophage polarization via the AMPK/mTOR autophagy pathway.

Objectives: Myocardial dysfunction is the most serious complication of sepsis. Sepsis-induced myocardial dysfunction (SIMD) is often associated with an excessive inflammatory response within the cardiac tissue. Targeted inhibition of the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) attenuates local tissue inflammatory responses. We investigated the efficacy of 11β-HSD1 blockade as a potential new treatment in SIMD.

Methods: In mice, sepsis was established by intraperitoneally injecting lipopolysaccharide (LPS, 10 mg/kg). Subsequently, the effects of 11β-HSD1 selective inhibitor BVT.2733 administration on LPS-triggered cardiac dysfunction, macrophage infiltration, and spleen inflammation in mice were investigated. In in vitro studies, the macrophage cell line RAW264.7 was used to assess the effect and molecular mechanism of BVT.2733 (50 or 100 μM) on LPS-induced polarization and inflammation. Furthermore, the supernatant of macrophages was collected after intervention and co-cultured with the H9C2 cell line to assess cardiomyocyte apoptosis and injury.

Results: The preventive administration of BVT.2733 can ameliorate cardiac dysfunction, M1 macrophage infiltration, and cardiac inflammation induced by LPS. The findings also demonstrated that BVT.2733 exhibited a mitigating effect on spleen pathological injury and inflammatory responses. Subsequently, BVT.2733 demonstrated the ability to inhibit M1 polarization of macrophages and attenuate inflammatory response in vitro. Meanwhile, our findings showed that BVT.2733 administration effectively mitigated inflammation and apoptosis in H9C2 cells in the proinflammatory environment produced by macrophages. Mechanistic studies revealed that BVT.2733 elevated autophagy levels by activating the AMPK/mTOR signaling pathway.

Conclusion: The 11β-HSD1 selective inhibitor BVT.2733 demonstrates potential in ameliorating cardiac dysfunction and myocardial injury in septic mice induced by LPS. This beneficial effect is likely attributed to the modulation of macrophage polarization through the AMPK/mTOR autophagy pathway.