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Inhibition of NFAT signaling restores microvascular endothelial function in diabetic mice

Garcia-Vaz, Eliana LU orcid ; McNeilly, Alison D. ; Berglund, Lisa M. LU ; Ahmad, Abrar LU ; Gallagher, Jennifer R. ; Andersson, Anna Maria Dutius LU ; McCrimmon, Rory J. ; Zetterqvist, Anna V. LU orcid ; Gomez, Maria F. LU orcid and Khan, Faisel (2020) In Diabetes 69(3). p.424-435
Abstract

Central to the development of diabetic macro- and microvascular disease is endothelial dysfunction, which appears well before any clinical sign but, importantly, is potentially reversible. We previously demonstrated that hyperglycemia activates nuclear factor of activated T cells (NFAT) in conduit and medium-sized resistance arteries and that NFAT blockade abolishes diabetes-driven aggravation of atherosclerosis. In this study, we test whether NFAT plays a role in the development of endothelial dysfunction in diabetes. NFAT-dependent transcriptional activity was elevated in skin microvessels of diabetic Akita (Ins21/2) mice when compared with nondiabetic littermates. Treatment of diabetic mice with the NFAT blocker... (More)

Central to the development of diabetic macro- and microvascular disease is endothelial dysfunction, which appears well before any clinical sign but, importantly, is potentially reversible. We previously demonstrated that hyperglycemia activates nuclear factor of activated T cells (NFAT) in conduit and medium-sized resistance arteries and that NFAT blockade abolishes diabetes-driven aggravation of atherosclerosis. In this study, we test whether NFAT plays a role in the development of endothelial dysfunction in diabetes. NFAT-dependent transcriptional activity was elevated in skin microvessels of diabetic Akita (Ins21/2) mice when compared with nondiabetic littermates. Treatment of diabetic mice with the NFAT blocker A-285222 reduced NFATc3 nuclear accumulation and NFAT-luciferase transcriptional activity in skin microvessels, resulting in improved microvascular function, as assessed by laser Doppler imaging and iontophoresis of acetylcholine and localized heating. This improvement was abolished by pretreatment with the nitric oxide (NO) synthase inhibitor L-NGnitro-L-arginine methyl ester, while iontophoresis of the NO donor sodium nitroprusside eliminated the observed differences. A-285222 treatment enhanced dermis endothelial NO synthase expression and plasma NO levels of diabetic mice. It also prevented induction of inflammatory cytokines interleukin-6 and osteopontin, lowered plasma endothelin-1 and blood pressure, and improved mouse survival without affecting blood glucose. In vivo inhibition of NFAT may represent a novel therapeutic modality to preserve endothelial function in diabetes.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
69
issue
3
pages
12 pages
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:85081142285
  • pmid:31806622
ISSN
0012-1797
DOI
10.2337/db18-0870
language
English
LU publication?
yes
id
372fc1ac-028e-4ce7-8a12-e63db467282e
date added to LUP
2021-01-05 11:11:12
date last changed
2024-06-13 03:28:56
@article{372fc1ac-028e-4ce7-8a12-e63db467282e,
  abstract     = {{<p>Central to the development of diabetic macro- and microvascular disease is endothelial dysfunction, which appears well before any clinical sign but, importantly, is potentially reversible. We previously demonstrated that hyperglycemia activates nuclear factor of activated T cells (NFAT) in conduit and medium-sized resistance arteries and that NFAT blockade abolishes diabetes-driven aggravation of atherosclerosis. In this study, we test whether NFAT plays a role in the development of endothelial dysfunction in diabetes. NFAT-dependent transcriptional activity was elevated in skin microvessels of diabetic Akita (Ins2<sup>1</sup>/<sup>2</sup>) mice when compared with nondiabetic littermates. Treatment of diabetic mice with the NFAT blocker A-285222 reduced NFATc3 nuclear accumulation and NFAT-luciferase transcriptional activity in skin microvessels, resulting in improved microvascular function, as assessed by laser Doppler imaging and iontophoresis of acetylcholine and localized heating. This improvement was abolished by pretreatment with the nitric oxide (NO) synthase inhibitor L-N<sup>G</sup>nitro-L-arginine methyl ester, while iontophoresis of the NO donor sodium nitroprusside eliminated the observed differences. A-285222 treatment enhanced dermis endothelial NO synthase expression and plasma NO levels of diabetic mice. It also prevented induction of inflammatory cytokines interleukin-6 and osteopontin, lowered plasma endothelin-1 and blood pressure, and improved mouse survival without affecting blood glucose. In vivo inhibition of NFAT may represent a novel therapeutic modality to preserve endothelial function in diabetes.</p>}},
  author       = {{Garcia-Vaz, Eliana and McNeilly, Alison D. and Berglund, Lisa M. and Ahmad, Abrar and Gallagher, Jennifer R. and Andersson, Anna Maria Dutius and McCrimmon, Rory J. and Zetterqvist, Anna V. and Gomez, Maria F. and Khan, Faisel}},
  issn         = {{0012-1797}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{424--435}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Inhibition of NFAT signaling restores microvascular endothelial function in diabetic mice}},
  url          = {{http://dx.doi.org/10.2337/db18-0870}},
  doi          = {{10.2337/db18-0870}},
  volume       = {{69}},
  year         = {{2020}},
}