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Neuraminidase inhibition improves endothelial function in diabetic mice.
Foote, Christopher A; Ramirez-Perez, Francisco I; Smith, James A; Ghiarone, Thaysa; Morales-Quinones, Mariana; McMillan, Neil J; Augenreich, Marc A; Power, Gavin; Burr, Katherine; Aroor, Annayya R; Bender, Shawn B; Manrique-Acevedo, Camila; Padilla, Jaume; Martinez-Lemus, Luis A.
Afiliação
  • Foote CA; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.
  • Ramirez-Perez FI; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, United States.
  • Smith JA; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.
  • Ghiarone T; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.
  • Morales-Quinones M; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States.
  • McMillan NJ; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.
  • Augenreich MA; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.
  • Power G; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.
  • Burr K; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States.
  • Aroor AR; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.
  • Bender SB; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States.
  • Manrique-Acevedo C; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.
  • Padilla J; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States.
  • Martinez-Lemus LA; NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.
Am J Physiol Heart Circ Physiol ; 325(6): H1337-H1353, 2023 12 01.
Article em En | MEDLINE | ID: mdl-37801046
Neuraminidases cleave sialic acids from glycocalyx structures and plasma neuraminidase activity is elevated in type 2 diabetes (T2D). Therefore, we hypothesize circulating neuraminidase degrades the endothelial glycocalyx and diminishes flow-mediated dilation (FMD), whereas its inhibition restores shear mechanosensation and endothelial function in T2D settings. We found that compared with controls, subjects with T2D have higher plasma neuraminidase activity, reduced plasma nitrite concentrations, and diminished FMD. Ex vivo and in vivo neuraminidase exposure diminished FMD and reduced endothelial glycocalyx presence in mouse arteries. In cultured endothelial cells, neuraminidase reduced glycocalyx coverage. Inhalation of the neuraminidase inhibitor, zanamivir, reduced plasma neuraminidase activity, enhanced endothelial glycocalyx length, and improved FMD in diabetic mice. In humans, a single-arm trial (NCT04867707) of zanamivir inhalation did not reduce plasma neuraminidase activity, improved glycocalyx length, or enhanced FMD. Although zanamivir plasma concentrations in mice reached 225.8 ± 22.0 ng/mL, in humans were only 40.0 ± 7.2 ng/mL. These results highlight the potential of neuraminidase inhibition for ameliorating endothelial dysfunction in T2D and suggest the current Food and Drug Administration-approved inhaled dosage of zanamivir is insufficient to achieve desired outcomes in humans.NEW & NOTEWORTHY This work identifies neuraminidase as a key mediator of endothelial dysfunction in type 2 diabetes that may serve as a biomarker for impaired endothelial function and predictive of development and progression of cardiovascular pathologies associated with type 2 diabetes (T2D). Data show that intervention with the neuraminidase inhibitor zanamivir at effective plasma concentrations may represent a novel pharmacological strategy for restoring the glycocalyx and ameliorating endothelial dysfunction.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças Vasculares / Diabetes Mellitus Experimental / Diabetes Mellitus Tipo 2 Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doenças Vasculares / Diabetes Mellitus Experimental / Diabetes Mellitus Tipo 2 Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article