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

Dongmei Zhu; Lingli Luo; Hanjie Zeng; Zheng Zhang; Min Huang; Suming Zhou

doi:10.7555/JBR.36.20220212

Article Contents

Article Navigation > The Journal of Biomedical Research > 2022 > Online Publication

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. 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. 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. doi: 10.7555/JBR.36.20220212

PDF( 14421 KB)

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

Department of Geriatrics Intensive Care Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China

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: 2022-11-30

Abstract

Abstract

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. The role of 11β-HSD1 in sepsis-induced myocardial dysfunction remains poorly understood. The current study aims to investigate the effects of 11β-HSD1 on a lipopolysaccharide (LPS)-induced mouse model. LPS (10 mg/kg) was administered to wild-type C57BL/6J mice and 11β-HSD1 global knockout mice. Cardiac function was assessed by echocardiography. Transmission electron microscopy and immunohistochemical staining were performed to analyze myocardial mitochondrial injury and histological changes. The levels of reactive oxygen species and biomarkers of oxidative stress were determined. Polymerase chain reaction analysis, Western blotting, and immunofluorescent staining were employed to determine the expression of related genes and proteins. To investigate the role of 11β-HSD1 in sepsis-induced myocardial dysfunction, LPS was used to induce lentivirus-infected neonatal rat ventricular cardiomyocytes. 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. The suppression of 11β-HSD1 may be a viable strategy to improve cardiac function against endotoxemia challenges.
- 11β-HSD1,
- LPS,
- sepsis-induced myocardial dysfunction,
- inflammation,
- oxidative stress

CLC number: 542.2, Document code: A
The authors reported no conflict of interests.

FullText(HTML)

References(26)

References

[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
[2]	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
[3]	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
[4]	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
[5]	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
[6]	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
[7]	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
[8]	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
[9]	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
[10]	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
[11]	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
[12]	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
[13]	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
[14]	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
[15]	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
[16]	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
[17]	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
[18]	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
[19]	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
[20]	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
[21]	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
[22]	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
[23]	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
[24]	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
[25]	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
[26]	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