Sphingosine-1-Phosphate Receptor Modulator, FTY720, Improves Diastolic Dysfunction and Partially Reverses Atrial Remodeling in a Tm-E180G Mouse Model Linked to Hypertrophic Cardiomyopathy.
Animals
Atrial Function, Left
/ drug effects
Atrial Remodeling
/ drug effects
Calcium Signaling
/ drug effects
Cardiomyopathy, Hypertrophic
/ drug therapy
Diastole
Disease Models, Animal
Female
Fibrosis
Fingolimod Hydrochloride
/ pharmacology
Genetic Predisposition to Disease
Male
Mice, Mutant Strains
Mutation
Myocytes, Cardiac
/ drug effects
Myofibrils
/ drug effects
Oxidative Stress
/ drug effects
Phenotype
Sphingosine 1 Phosphate Receptor Modulators
/ pharmacology
Sphingosine-1-Phosphate Receptors
/ drug effects
Tropomyosin
/ genetics
cardiac myosin
cardiomyopathy, hypertrophic
sphingosine
tropomyosin
Journal
Circulation. Heart failure
ISSN: 1941-3297
Titre abrégé: Circ Heart Fail
Pays: United States
ID NLM: 101479941
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
entrez:
6
11
2019
pubmed:
7
11
2019
medline:
17
6
2020
Statut:
ppublish
Résumé
Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder, primarily involving mutations in sarcomeric proteins. HCM patients present with hypertrophy, diastolic dysfunction, and fibrosis, but there is no specific treatment. The sphingosine-1-phosphate receptor modulator, FTY720/fingolimod, is approved for treatment of multiple sclerosis. We hypothesize that modulation of the sphingosine-1-phosphate receptor by FTY720 would be of therapeutic benefit in sarcomere-linked HCM. We treated mice with an HCM-linked mutation in tropomyosin (Tm-E180G) and nontransgenic littermates with FTY720 or vehicle for 6 weeks. Compared with vehicle-treated, FTY720-treated Tm-E180G mice had a significant reduction in left atrial size (1.99±0.19 [n=7] versus 2.70±0.44 [n=6] mm; Pressure-volume relations revealed significant improvements in the end-diastolic pressure volume relationship, relaxation kinetics, preload recruitable stroke work, and ejection fraction. Detergent-extracted fiber bundles revealed a significant decrease in myofilament Ca This is the first demonstration that modulation of S1PR results in decreased myofilament-Ca
Sections du résumé
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder, primarily involving mutations in sarcomeric proteins. HCM patients present with hypertrophy, diastolic dysfunction, and fibrosis, but there is no specific treatment. The sphingosine-1-phosphate receptor modulator, FTY720/fingolimod, is approved for treatment of multiple sclerosis. We hypothesize that modulation of the sphingosine-1-phosphate receptor by FTY720 would be of therapeutic benefit in sarcomere-linked HCM.
METHODS
We treated mice with an HCM-linked mutation in tropomyosin (Tm-E180G) and nontransgenic littermates with FTY720 or vehicle for 6 weeks. Compared with vehicle-treated, FTY720-treated Tm-E180G mice had a significant reduction in left atrial size (1.99±0.19 [n=7] versus 2.70±0.44 [n=6] mm;
RESULTS
Pressure-volume relations revealed significant improvements in the end-diastolic pressure volume relationship, relaxation kinetics, preload recruitable stroke work, and ejection fraction. Detergent-extracted fiber bundles revealed a significant decrease in myofilament Ca
CONCLUSIONS
This is the first demonstration that modulation of S1PR results in decreased myofilament-Ca
Identifiants
pubmed: 31684756
doi: 10.1161/CIRCHEARTFAILURE.118.005835
pmc: PMC6857720
mid: NIHMS1540640
doi:
Substances chimiques
Sphingosine 1 Phosphate Receptor Modulators
0
Sphingosine-1-Phosphate Receptors
0
Tropomyosin
0
Fingolimod Hydrochloride
G926EC510T
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e005835Subventions
Organisme : NHLBI NIH HHS
ID : P01 HL062426
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK109015
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128468
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020595
Pays : United States
Organisme : NIDDK NIH HHS
ID : P60 DK020595
Pays : United States
Organisme : NHLBI NIH HHS
ID : F31 HL127996
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007692
Pays : United States
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