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Suppression of Hypoxia-Inducible Factor 1α by Low-Molecular-Weight Heparin Mitigates Ventilation-Induced Diaphragm Dysfunction in a Murine Endotoxemia Model

1
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
2
Department of Internal Medicine, Chang Gung University, Taoyuan 33302, Taiwan
3
Department of Respiratory Therapy, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
4
Chest Department, Taipei Veterans General Hospital, Taipei 11217, Taiwan
5
Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan
6
Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editor: Michele Samaja
Int. J. Mol. Sci. 2021, 22(4), 1702; https://doi.org/10.3390/ijms22041702
Received: 12 January 2021 / Revised: 3 February 2021 / Accepted: 5 February 2021 / Published: 8 February 2021
(This article belongs to the Section Molecular Biology)
Mechanical ventilation (MV) is required to maintain life for patients with sepsis-related acute lung injury but can cause diaphragmatic myotrauma with muscle damage and weakness, known as ventilator-induced diaphragm dysfunction (VIDD). Hypoxia-inducible factor 1α (HIF-1α) plays a crucial role in inducing inflammation and apoptosis. Low-molecular-weight heparin (LMWH) was proven to have anti-inflammatory properties. However, HIF-1α and LMWH affect sepsis-related diaphragm injury has not been investigated. We hypothesized that LMWH would reduce endotoxin-augmented VIDD through HIF-1α. C57BL/6 mice, either wild-type or HIF-1α–deficient, were exposed to MV with or without endotoxemia for 8 h. Enoxaparin (4 mg/kg) was administered subcutaneously 30 min before MV. MV with endotoxemia aggravated VIDD, as demonstrated by increased interleukin-6 and macrophage inflammatory protein-2 levels, oxidative loads, and the expression of HIF-1α, calpain, caspase-3, atrogin-1, muscle ring finger-1, and microtubule-associated protein light chain 3-II. Disorganized myofibrils, disrupted mitochondria, increased numbers of autophagic and apoptotic mediators, substantial apoptosis of diaphragm muscle fibers, and decreased diaphragm function were also observed (p < 0.05). Endotoxin-exacerbated VIDD and myonuclear apoptosis were attenuated by pharmacologic inhibition by LMWH and in HIF-1α–deficient mice (p < 0.05). Our data indicate that enoxaparin reduces endotoxin-augmented MV-induced diaphragmatic injury, partially through HIF-1α pathway inhibition. View Full-Text
Keywords: endotoxemia; hypoxia-inducible factor-1α; low-molecular-weight heparin; mitochondria; ventilator-induced diaphragm dysfunction endotoxemia; hypoxia-inducible factor-1α; low-molecular-weight heparin; mitochondria; ventilator-induced diaphragm dysfunction
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MDPI and ACS Style

Li, L.-F.; Yu, C.-C.; Huang, H.-Y.; Wu, H.-P.; Chu, C.-M.; Huang, C.-Y.; Liu, P.-C.; Liu, Y.-Y. Suppression of Hypoxia-Inducible Factor 1α by Low-Molecular-Weight Heparin Mitigates Ventilation-Induced Diaphragm Dysfunction in a Murine Endotoxemia Model. Int. J. Mol. Sci. 2021, 22, 1702. https://doi.org/10.3390/ijms22041702

AMA Style

Li L-F, Yu C-C, Huang H-Y, Wu H-P, Chu C-M, Huang C-Y, Liu P-C, Liu Y-Y. Suppression of Hypoxia-Inducible Factor 1α by Low-Molecular-Weight Heparin Mitigates Ventilation-Induced Diaphragm Dysfunction in a Murine Endotoxemia Model. International Journal of Molecular Sciences. 2021; 22(4):1702. https://doi.org/10.3390/ijms22041702

Chicago/Turabian Style

Li, Li-Fu, Chung-Chieh Yu, Hung-Yu Huang, Huang-Pin Wu, Chien-Ming Chu, Chih-Yu Huang, Ping-Chi Liu, and Yung-Yang Liu. 2021. "Suppression of Hypoxia-Inducible Factor 1α by Low-Molecular-Weight Heparin Mitigates Ventilation-Induced Diaphragm Dysfunction in a Murine Endotoxemia Model" International Journal of Molecular Sciences 22, no. 4: 1702. https://doi.org/10.3390/ijms22041702

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