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Updated: Jul 19, 2026
Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies
Published on: April 11, 2012
11β-HSD1 inhibitor alleviates sepsis-induced cardiac dysfunction by regulating macrophage polarization via the
Zheng Zhang1, Binghui Yin2, Dongmei Zhu2
1Department of Emergency Medicine, the First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, 210029, China; Critical Care Center, the First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
Insights
Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with BVT.2733 ameliorates sepsis-induced myocardial dysfunction in mice. This treatment reduces cardiac inflammation and macrophage infiltration by modulating macrophage polarization via the AMPK/mTOR autophagy pathway.
Area of Science:
- Cardiovascular Research
- Immunology
- Pharmacology
Background:
- Sepsis-induced myocardial dysfunction (SIMD) is a severe complication driven by cardiac inflammation.
- 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition can reduce local tissue inflammation.
Purpose of the Study:
- To investigate the efficacy of the 11β-HSD1 inhibitor BVT.2733 as a potential treatment for SIMD.
Main Methods:
- Sepsis was induced in mice using lipopolysaccharide (LPS).
- The effects of BVT.2733 on cardiac dysfunction, macrophage infiltration, and spleen inflammation were assessed.
- In vitro studies used RAW264.7 macrophages and H9C2 cardiomyocytes to examine BVT.2733's molecular mechanisms and effects on inflammation and apoptosis.
Main Results:
- BVT.2733 administration ameliorated LPS-induced cardiac dysfunction, M1 macrophage infiltration, and cardiac inflammation in mice.
- The inhibitor reduced spleen injury and inflammation, inhibited M1 macrophage polarization in vitro, and decreased cardiomyocyte apoptosis.
- Mechanistic studies indicated BVT.2733 activates the AMPK/mTOR signaling pathway, increasing autophagy.
Conclusions:
- The 11β-HSD1 inhibitor BVT.2733 shows promise for treating SIMD and LPS-induced myocardial injury in mice.
- Therapeutic benefits are linked to modulating macrophage polarization through the AMPK/mTOR-mediated 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.
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