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Fibrinogen in mice cerebral microvessels induces blood-brain barrier dysregulation with aging via a dynamin-related protein 1-dependent pathway.
Chandra, Partha K; Panner Selvam, Manesh Kumar; Castorena-Gonzalez, Jorge A; Rutkai, Ibolya; Sikka, Suresh C; Mostany, Ricardo; Busija, David W.
Afiliación
  • Chandra PK; Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA. pchandr1@tulane.edu.
  • Panner Selvam MK; Tulane Brain Institute, Tulane University, 200 Flower Hall, 6823 St. Charles Avenue, New Orleans, LA, 70118, USA. pchandr1@tulane.edu.
  • Castorena-Gonzalez JA; Department of Urology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA.
  • Rutkai I; Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA.
  • Sikka SC; Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA.
  • Mostany R; Tulane Brain Institute, Tulane University, 200 Flower Hall, 6823 St. Charles Avenue, New Orleans, LA, 70118, USA.
  • Busija DW; Department of Urology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA.
Geroscience ; 46(1): 395-415, 2024 Feb.
Article en En | MEDLINE | ID: mdl-37897653
We previously reported evidence that oxidative stress during aging leads to adverse protein profile changes of brain cortical microvessels (MVs: end arterioles, capillaries, and venules) that affect mRNA/protein stability, basement membrane integrity, and ATP synthesis capacity in mice. As an extension of our previous study, we also found that proteins which comprise the blood-brain barrier (BBB) and regulate mitochondrial quality control were also significantly decreased in the mice's cortical MVs with aging. Interestingly, the neuroinflammatory protein fibrinogen (Fgn) was increased in mice brain MVs, which corresponds with clinical reports indicating that the plasma Fgn concentration increased progressively with aging. In this study, protein-protein interaction network analysis indicated that high expression of Fgn is linked with downregulated expression of both BBB- and mitochondrial fission/fusion-related proteins in mice cortical MVs with aging. To investigate the mechanism of Fgn action, we observed that 2 mg/mL or higher concentration of human plasma Fgn changed cell morphology, induced cytotoxicity, and increased BBB permeability in primary human brain microvascular endothelial cells (HBMECs). The BBB tight junction proteins were significantly decreased with increasing concentration of human plasma Fgn in primary HBMECs. Similarly, the expression of phosphorylated dynamin-related protein 1 (pDRP1) and other mitochondrial fission/fusion-related proteins were also significantly reduced in Fgn-treated HBMECs. Interestingly, DRP1 knockdown by shRNA(h) resulted in the reduction of both BBB- and mitochondrial fission/fusion-related proteins in HBMECs. Our results suggest that elevated Fgn downregulates DRP1, leading to mitochondrial-dependent endothelial and BBB dysfunction in the brain microvasculature.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Células Endoteliales Límite: Animals / Humans Idioma: En Revista: Geroscience Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Barrera Hematoencefálica / Células Endoteliales Límite: Animals / Humans Idioma: En Revista: Geroscience Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza