Administration of a TLR9 Inhibitor Attenuates the Development and Progression of Heart Failure in Mice.
CCCP, carbonyl cyanide m-chlorophenyl hydrazine
CpG ODN, unmethylated cytidine-phosphate-guanosine containing oligodeoxynucleotide
CpG, cytidine-phosphate-guanosine
DNA, deoxyribonucleic acid
E6446, (6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole)
EdU, 5-ethynyl-2′-deoxyuridine
IL, interleukin
IVSd, end-diastolic interventricular septal wall thickness
LAMP, lysosome-associated membrane protein
LC, microtubule-associated protein light chain
LPS, lipopolysaccharide
LV, left ventricular
TAC, transverse aortic constriction
TLR, Toll-like receptor
TNF, tumor necrosis factor
Toll-like receptor 9
heart failure
mRNA, messenger ribonucleic acid
mitochondria
pressure overload
Journal
JACC. Basic to translational science
ISSN: 2452-302X
Titre abrégé: JACC Basic Transl Sci
Pays: United States
ID NLM: 101677259
Informations de publication
Date de publication:
Jun 2019
Jun 2019
Historique:
received:
03
10
2018
revised:
10
01
2019
accepted:
11
01
2019
entrez:
18
7
2019
pubmed:
18
7
2019
medline:
18
7
2019
Statut:
epublish
Résumé
Mitochondrial deoxyribonucleic acid, containing the unmethylated cytidine-phosphate-guanosine motif, stimulates Toll-like receptor 9 to induce inflammation and heart failure. A small chemical, E6446 [(6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole)], is a specific Toll-like receptor 9 inhibitor in cardiomyocytes. In this study, we showed that E6446 exerts beneficial effects for the prevention and treatment of pressure overload-induced heart failure in mice. When administered before the operation and chronically thereafter, E6446 prevented the development of left ventricular dilatation as well as cardiac dysfunction, fibrosis, and inflammation. Furthermore, when administered after the manifestation of cardiac dysfunction, E6446 slowed progression of cardiac remodeling. Thus, the inhibitor may be a novel therapeutic agent for treating patients with heart failure.
Identifiants
pubmed: 31312759
doi: 10.1016/j.jacbts.2019.01.002
pii: S2452-302X(19)30009-9
pmc: PMC6610159
doi:
Types de publication
Journal Article
Langues
eng
Pagination
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