Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO.
Animals
Aorta
/ cytology
Aortic Aneurysm, Thoracic
/ diagnosis
Biomarkers
/ blood
Carbazoles
/ administration & dosage
Cyclic GMP
/ blood
Cyclic GMP-Dependent Protein Kinase Type I
/ metabolism
Disease Models, Animal
Female
Fibrillin-1
/ genetics
Gene Knockdown Techniques
Humans
Male
Marfan Syndrome
/ blood
Mice
Muscle, Smooth, Vascular
/ cytology
Mutation
Myocytes, Smooth Muscle
Nitric Oxide
/ metabolism
Nitric Oxide Donors
/ administration & dosage
Primary Cell Culture
Soluble Guanylyl Cyclase
/ antagonists & inhibitors
Ultrasonography
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 05 2021
11 05 2021
Historique:
received:
21
05
2020
accepted:
01
04
2021
entrez:
12
5
2021
pubmed:
13
5
2021
medline:
27
5
2021
Statut:
epublish
Résumé
Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.
Identifiants
pubmed: 33976159
doi: 10.1038/s41467-021-22933-3
pii: 10.1038/s41467-021-22933-3
pmc: PMC8113458
doi:
Substances chimiques
Biomarkers
0
Carbazoles
0
Fbn1 protein, mouse
0
Fibrillin-1
0
Nitric Oxide Donors
0
KT 5823
126643-37-6
Nitric Oxide
31C4KY9ESH
Cyclic GMP-Dependent Protein Kinase Type I
EC 2.7.11.12
PRKG1 protein, human
EC 2.7.11.12
Prkg1 protein, mouse
EC 2.7.11.12
Soluble Guanylyl Cyclase
EC 4.6.1.2
Cyclic GMP
H2D2X058MU
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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