دورية أكاديمية
Inflammatory lung injury is associated with endothelial cell mitochondrial fission and requires the nitration of RhoA and cytoskeletal remodeling.
العنوان: | Inflammatory lung injury is associated with endothelial cell mitochondrial fission and requires the nitration of RhoA and cytoskeletal remodeling. |
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المؤلفون: | Pokharel MD; Department of Cellular & Molecular Medicine, Herbert Wertheim College of Medicine, Miami, FL, USA; Center for Translational Science, Florida International University, Port St. Lucie, FL, USA., Fu P; Center for Translational Science, Florida International University, Port St. Lucie, FL, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, University Park, FL, USA., Garcia-Flores A; Center for Translational Science, Florida International University, Port St. Lucie, FL, USA., Yegambaram M; Center for Translational Science, Florida International University, Port St. Lucie, FL, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, University Park, FL, USA., Lu Q; Center for Translational Science, Florida International University, Port St. Lucie, FL, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, University Park, FL, USA., Sun X; Center for Translational Science, Florida International University, Port St. Lucie, FL, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, University Park, FL, USA., Unwalla H; Department of Immunology and Nano-Medicine, Howard Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA., Aggarwal S; Department of Cellular & Molecular Medicine, Herbert Wertheim College of Medicine, Miami, FL, USA., Fineman JR; Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA; Department of Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, 94143, USA., Wang T; Center for Translational Science, Florida International University, Port St. Lucie, FL, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, University Park, FL, USA., Black SM; Department of Cellular & Molecular Medicine, Herbert Wertheim College of Medicine, Miami, FL, USA; Center for Translational Science, Florida International University, Port St. Lucie, FL, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, University Park, FL, USA. Electronic address: stblack@fiu.edu. |
المصدر: | Free radical biology & medicine [Free Radic Biol Med] 2024 Aug 20; Vol. 221, pp. 125-135. Date of Electronic Publication: 2024 May 10. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Elsevier Science Country of Publication: United States NLM ID: 8709159 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4596 (Electronic) Linking ISSN: 08915849 NLM ISO Abbreviation: Free Radic Biol Med Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Tarrytown, NY : Elsevier Science Original Publication: New York : Pergamon, c1987- |
مواضيع طبية MeSH: | Mitochondrial Dynamics* , rhoA GTP-Binding Protein*/metabolism , Endothelial Cells*/metabolism , Endothelial Cells*/pathology , Endothelial Cells*/drug effects , Toll-Like Receptor 4*/metabolism , Toll-Like Receptor 4*/genetics , rho-Associated Kinases*/metabolism , Cytoskeleton*/metabolism , Acute Lung Injury*/metabolism , Acute Lung Injury*/pathology, Animals ; Mice ; Humans ; Mitochondria/metabolism ; Mitochondria/pathology ; Mice, Inbred C57BL ; Lipopolysaccharides ; Male ; Signal Transduction |
مستخلص: | Higher levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a TLR4 agonist, are associated with poor clinical outcomes in sepsis-induced acute lung injury (ALI). Little is known regarding the mechanisms by which eNAMPT is involved in ALI. Our recent work has identified a crucial role for mitochondrial dysfunction in ALI. Thus, this study aimed to determine if eNAMPT-mediated inflammatory injury is associated with the loss of mitochondrial function. Our data show that eNAMPT disrupted mitochondrial bioenergetics. This was associated with cytoskeleton remodeling and the loss of endothelial barrier integrity. These changes were associated with enhanced mitochondrial fission and blocked when Rho-kinase (ROCK) was inhibited. The increases in mitochondrial fission were also associated with the nitration-mediated activation of the small GTPase activator of ROCK, RhoA. Blocking RhoA nitration decreased eNAMPT-mediated mitochondrial fission and endothelial barrier dysfunction. The increase in fission was linked to a RhoA-ROCK mediated increase in Drp1 (dynamin-related protein 1) at serine(S) 616 . Another TLR4 agonist, lipopolysaccharide (LPS), also increased mitochondrial fission in a Drp1 and RhoA-ROCK-dependent manner. To validate our findings in vivo, we challenged C57BL/6 mice with eNAMPT in the presence and absence of the Drp1 inhibitor, Mdivi-1. Mdivi-1 treatment protected against eNAMPT-induced lung inflammation, edema, and lung injury. These studies demonstrate that mitochondrial fission-dependent disruption of mitochondrial function is essential in TLR4-mediated inflammatory lung injury and identify a key role for RhoA-ROCK signaling. Reducing mitochondrial fission could be a potential therapeutic strategy to improve ARDS outcomes. Competing Interests: Declaration of competing interest None. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
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معلومات مُعتمدة: | P01 HL146369 United States HL NHLBI NIH HHS; P01 HL134610 United States HL NHLBI NIH HHS; R01 HL142212 United States HL NHLBI NIH HHS; U01 ES033265 United States ES NIEHS NIH HHS; R01 HL137282 United States HL NHLBI NIH HHS; R01 HL060190 United States HL NHLBI NIH HHS |
فهرسة مساهمة: | Keywords: Acute lung injury; Cytoskeleton; Endothelial cell; Mitochondrial bioenergetics; Mitochondrial fission; ROS |
المشرفين على المادة: | EC 3.6.5.2 (rhoA GTP-Binding Protein) 0 (Toll-Like Receptor 4) EC 2.7.11.1 (rho-Associated Kinases) EC 3.6.5.2 (RhoA protein, mouse) 0 (Lipopolysaccharides) 0 (Tlr4 protein, mouse) 124671-05-2 (RHOA protein, human) |
تواريخ الأحداث: | Date Created: 20240511 Date Completed: 20240614 Latest Revision: 20240709 |
رمز التحديث: | 20240709 |
مُعرف محوري في PubMed: | PMC11179967 |
DOI: | 10.1016/j.freeradbiomed.2024.05.019 |
PMID: | 38734269 |
قاعدة البيانات: | MEDLINE |
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