Impact Factor
  • ISSN 1674-8301
  • CN 32-1810/R
Volume 37 Issue 4
Jul.  2023
Turn off MathJax
Article Contents
Dongmei Zhu, Lingli Luo, Hanjie Zeng, Zheng Zhang, Min Huang, Suming Zhou. Knockdown of 11β-hydroxysteroid dehydrogenase type 1 alleviates LPS-induced myocardial dysfunction through the AMPK/SIRT1/PGC-1α pathway[J]. The Journal of Biomedical Research, 2023, 37(4): 290-301. doi: 10.7555/JBR.36.20220212
Citation: Dongmei Zhu, Lingli Luo, Hanjie Zeng, Zheng Zhang, Min Huang, Suming Zhou. Knockdown of 11β-hydroxysteroid dehydrogenase type 1 alleviates LPS-induced myocardial dysfunction through the AMPK/SIRT1/PGC-1α pathway[J]. The Journal of Biomedical Research, 2023, 37(4): 290-301. doi: 10.7555/JBR.36.20220212

Knockdown of 11β-hydroxysteroid dehydrogenase type 1 alleviates LPS-induced myocardial dysfunction through the AMPK/SIRT1/PGC-1α pathway

doi: 10.7555/JBR.36.20220212
More Information
  • Corresponding author: Min Huang and Suming Zhou, Department of Geriatrics Intensive Care Unit, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China. Tels: +86-25-68305051 and +86-25-68305053, E-mails: hmdoctor@163.com and zhousmco@aliyun.com
  • Received: 2022-09-25
  • Revised: 2022-11-13
  • Accepted: 2022-11-22
  • Published: 2023-05-29
  • Issue Date: 2023-07-28
  • Sepsis-induced myocardial dysfunction is primarily accompanied by severe sepsis, which is associated with high morbidity and mortality. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), encoded by Hsd11b1, is a reductase that can convert inactive cortisone into metabolically active cortisol, but the role of 11β-HSD1 in sepsis-induced myocardial dysfunction remains poorly understood. The current study aimed to investigate the effects of 11β-HSD1 on a lipopolysaccharide (LPS)-induced mouse model, in which LPS (10 mg/kg) was administered to wild-type C57BL/6J mice and 11β-HSD1 global knockout mice. We asscessed cardiac function by echocardiography, performed transmission electron microscopy and immunohistochemical staining to analyze myocardial mitochondrial injury and histological changes, and determined the levels of reactive oxygen species and biomarkers of oxidative stress. We also employed polymerase chain reaction analysis, Western blotting, and immunofluorescent staining to determine the expression of related genes and proteins. To investigate the role of 11β-HSD1 in sepsis-induced myocardial dysfunction, we used LPS to induce lentivirus-infected neonatal rat ventricular cardiomyocytes. We found that knockdown of 11β-HSD1 alleviated LPS-induced myocardial mitochondrial injury, oxidative stress, and inflammation, along with an improved myocardial function; furthermore, the depletion of 11β-HSD1 promoted the phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), and silent information regulator 1 (SIRT1) protein levels both in vivo and in vitro. Therefore, the suppression of 11β-HSD1 may be a viable strategy to improve cardiac function against endotoxemia challenges.


  • CLC number: 542.2, Document code: A
    The authors reported no conflict of interests.
  • loading
  • [1]
    Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021[J]. Crit Care Med, 2021, 49(11): e1063–e1143. doi: 10.1097/CCM.0000000000005337
    Wang R, Xu Y, Fang Y, et al. Pathogenetic mechanisms of septic cardiomyopathy[J]. J Cell Physiol, 2022, 237(1): 49–58. doi: 10.1002/jcp.30527
    Ehrman RR, Sullivan AN, Favot MJ, et al. Pathophysiology, echocardiographic evaluation, biomarker findings, and prognostic implications of septic cardiomyopathy: a review of the literature[J]. Crit Care, 2018, 22(1): 112. doi: 10.1186/s13054-018-2043-8
    De Castro R, Ruiz D, Lavín BA, et al. Cortisol and adrenal androgens as independent predictors of mortality in septic patients[J]. PLoS One, 2019, 14(4): e0214312. doi: 10.1371/journal.pone.0214312
    Gomez-Sanchez EP, Gomez-Sanchez CE. 11β-hydroxysteroid dehydrogenases: A growing multi-tasking family[J]. Mol Cell Endocrinol, 2021, 526: 111210. doi: 10.1016/j.mce.2021.111210
    Cohen J, Blumenthal A, Cuellar-Partida G, et al. The relationship between adrenocortical candidate gene expression and clinical response to hydrocortisone in patients with septic shock[J]. Intensive Care Med, 2021, 47(9): 974–983. doi: 10.1007/s00134-021-06464-5
    McSweeney SJ, Hadoke PWF, Kozak AM, et al. Improved heart function follows enhanced inflammatory cell recruitment and angiogenesis in 11betaHSD1-deficient mice post-MI[J]. Cardiovasc Res, 2010, 88(1): 159–167. doi: 10.1093/cvr/cvq149
    Mylonas KJ, Turner NA, Bageghni SA, et al. 11β-HSD1 suppresses cardiac fibroblast CXCL2, CXCL5 and neutrophil recruitment to the heart post MI[J]. J Endocrinol, 2017, 233(3): 315–327. doi: 10.1530/JOE-16-0501
    Huang M, Liu J, Sheng Y, et al. 11β-hydroxysteroid dehydrogenase type 1 inhibitor attenuates high-fat diet induced cardiomyopathy[J]. J Mol Cell Cardiol, 2018, 125: 106–116. doi: 10.1016/j.yjmcc.2018.10.002
    Sun Y, Yao X, Zhang Q, et al. Beclin-1-dependent autophagy protects the heart during sepsis[J]. Circulation, 2018, 138(20): 2247–2262. doi: 10.1161/CIRCULATIONAHA.117.032821
    Koentges C, Cimolai MC, Pfeil K, et al. Impaired SIRT3 activity mediates cardiac dysfunction in endotoxemia by calpain-dependent disruption of ATP synthesis[J]. J Mol Cell Cardiol, 2019, 133: 138–147. doi: 10.1016/j.yjmcc.2019.06.008
    Shao S, Zhang X, Zhang M. Inhibition of 11β-hydroxysteroid dehydrogenase type 1 ameliorates obesity-related insulin resistance[J]. Biochem Biophys Res Commun, 2016, 478(1): 474–480. doi: 10.1016/j.bbrc.2016.06.015
    Wang L, Liu J, Zhang A, et al. BVT. 2733, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice[J]. PLoS One, 2012, 7(7): e40056. doi: 10.1371/journal.pone.0040056
    Koh EH, Kim AR, Kim H, et al. 11β-HSD1 reduces metabolic efficacy and adiponectin synthesis in hypertrophic adipocytes[J]. J Endocrinol, 2015, 225(3): 147–158. doi: 10.1530/JOE-15-0117
    Haileselassie B, Su E, Pozios I, et al. Myocardial oxidative stress correlates with left ventricular dysfunction on strain echocardiography in a rodent model of sepsis[J]. Intensive Care Med Exp, 2017, 5(1): 21. doi: 10.1186/s40635-017-0134-5
    Miliaraki M, Briassoulis P, Ilia S, et al. Oxidant/antioxidant status is impaired in sepsis and is related to anti-apoptotic, inflammatory, and innate immunity alterations[J]. Antioxidants (Basel), 2022, 11(2): 231. doi: 10.3390/antiox11020231
    Marino A, Hausenloy DJ, Andreadou I, et al. AMP-activated protein kinase: a remarkable contributor to preserve a healthy heart against ROS injury[J]. Free Radic Biol Med, 2021, 166: 238–254. doi: 10.1016/j.freeradbiomed.2021.02.047
    Xu W, Yan J, Ocak U, et al. Melanocortin 1 receptor attenuates early brain injury following subarachnoid hemorrhage by controlling mitochondrial metabolism via AMPK/SIRT1/PGC-1α pathway in rats[J]. Theranostics, 2021, 11(2): 522–539. doi: 10.7150/thno.49426
    White CI, Jansen MA, McGregor K, et al. Cardiomyocyte and vascular smooth muscle-independent 11β-hydroxysteroid dehydrogenase 1 amplifies infarct expansion, hypertrophy, and the development of heart failure after myocardial infarction in male mice[J]. Endocrinology, 2016, 157(1): 346–357. doi: 10.1210/en.2015-1630
    Park SB, Park JS, Jung WH, et al. Anti-inflammatory effect of a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor via the stimulation of heme oxygenase-1 in LPS-activated mice and J774.1 murine macrophages[J]. J Pharmacol Sci, 2016, 131(4): 241–250. doi: 10.1016/j.jphs.2016.07.003
    Letts JA, Sazanov LA. Clarifying the supercomplex: the higher-order organization of the mitochondrial electron transport chain[J]. Nat Struct Mol Biol, 2017, 24(10): 800–808. doi: 10.1038/nsmb.3460
    Vico TA, Marchini T, Ginart S, et al. Mitochondrial bioenergetics links inflammation and cardiac contractility in endotoxemia[J]. Basic Res Cardiol, 2019, 114(5): 38. doi: 10.1007/s00395-019-0745-y
    Liu J, Kong X, Wang L, et al. Essential roles of 11β-HSD1 in regulating brown adipocyte function[J]. J Mol Endocrinol, 2013, 50(1): 103–113. doi: 10.1530/JME-12-0099
    Rius-Pérez S, Torres-Cuevas I, Millán I, et al. PGC-1α, inflammation, and oxidative stress: an integrative view in metabolism[J]. Oxid Med Cell Longev, 2020, 2020: 1452696. doi: 10.1155/2020/1452696
    Wang Y, Zhao X, Lotz M, et al. Mitochondrial biogenesis is impaired in osteoarthritis chondrocytes but reversible via peroxisome proliferator-activated receptor γ coactivator 1α[J]. Arthritis Rheumatol, 2015, 67(8): 2141–2153. doi: 10.1002/art.39182
    Hong G, Zheng D, Zhang L, et al. Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis[J]. Free Radic Biol Med, 2018, 123: 125–137. doi: 10.1016/j.freeradbiomed.2018.05.073
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (1555) PDF downloads(120) Cited by()
    Proportional views
    Relative Articles


    DownLoad:  Full-Size Img  PowerPoint