Targeting exosome-associated human antigen R attenuates fibrosis and inflammation in diabetic heart.
HuR
cardiac fibrosis
cardiac inflammation
diabetes
exosome
intercellular signaling
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
08
08
2019
revised:
14
11
2019
accepted:
21
11
2019
pubmed:
8
1
2020
medline:
29
9
2020
entrez:
8
1
2020
Statut:
ppublish
Résumé
RNA-binding proteins like human antigen R (HuR) are key regulators in post-transcriptional control of gene expression in several pathophysiological conditions. Diabetes adversely affects monocyte/macrophage biology and function. It is not known whether diabetic milieu affects cellular/exosome-HuR and its implications on cardiac inflammation and fibrosis. Here, we evaluate in vitro and in vivo effects of diabetic milieu on macrophage cellular/exosome-HuR, alterations in intercellular cross talk with fibroblasts, and its impact on cardiac remodeling. Human failing hearts show higher HuR levels. Diabetic milieu activates HuR expression in cardiac- and cultured bone marrow-derived macrophages (BMMØ) and stimulates HuR nuclear-to-cytoplasmic translocation and exosome transfer. Exosomes from macrophages exposed to diabetic milieu (high glucose or db/db mice) significantly increase inflammatory and profibrogenic responses in fibroblast (in vitro) and cardiac fibrosis in mice. Intriguingly, Exo-HuR deficiency (HuR knockdown in macrophage) abrogates the above effects. In diabetic mice, macrophage depletion followed by reconstitution with BMMØ-derived HuR-deficient exosomes inhibits angiotensin II-induced cardiac fibrosis response and preserves left ventricle function as compared to control-exosome administration. To the best of our knowledge, this is the first study to demonstrate that diabetes activates BMMØ HuR expression and its transfer into exosome. The data suggest that HuR might be targeted to alleviate macrophage dysfunction and pathological fibrosis in diabetes.
Identifiants
pubmed: 31907992
doi: 10.1096/fj.201901995R
pmc: PMC8286699
mid: NIHMS1590475
doi:
Substances chimiques
ELAV-Like Protein 1
0
Elavl1 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2238-2251Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL126186
Pays : United States
Organisme : American Heart Association-American Stroke Association
ID : 0930219N
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL138023
Pays : United States
Organisme : HHS | National Institutes of Health (NIH)
ID : HL116729
Pays : International
Organisme : NIDDK NIH HHS
ID : P30 DK079626
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL116729
Pays : United States
Organisme : HHS | National Institutes of Health (NIH)
ID : HL134608
Pays : International
Organisme : HHS | National Institutes of Health (NIH)
ID : HL126186
Pays : International
Organisme : NHLBI NIH HHS
ID : R56 HL142627
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL134608
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142627
Pays : United States
Organisme : HHS | National Institutes of Health (NIH)
ID : HL138023
Pays : International
Informations de copyright
© 2019 Federation of American Societies for Experimental Biology.
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