Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance.
Animals
Desoxycorticosterone Acetate
/ pharmacology
Diastole
/ drug effects
Disease Models, Animal
Heart Failure
/ drug therapy
Heart Ventricles
/ drug effects
Male
Metformin
/ pharmacology
Mice
Mice, Inbred C57BL
Myocardium
/ metabolism
Phosphorylation
/ drug effects
Protein Kinases
/ metabolism
Stroke Volume
/ drug effects
Journal
The Journal of general physiology
ISSN: 1540-7748
Titre abrégé: J Gen Physiol
Pays: United States
ID NLM: 2985110R
Informations de publication
Date de publication:
07 01 2019
07 01 2019
Historique:
received:
25
09
2018
accepted:
14
11
2018
pubmed:
21
12
2018
medline:
20
3
2020
entrez:
21
12
2018
Statut:
ppublish
Résumé
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by a preserved ejection fraction but increased diastolic stiffness and abnormalities of filling. Although the prevalence of HFpEF is high and continues to rise, no effective therapies exist; however, the diabetic drug metformin has been associated with improved diastolic function in diabetic patients. Here we determine the therapeutic potential of metformin for improving diastolic function in a mouse model with HFpEF-like symptoms. We combine transverse aortic constriction (TAC) surgery with deoxycorticosterone acetate (DOCA) supplementation to obtain a mouse model with increased diastolic stiffness and exercise intolerance. Echocardiography and pressure-volume analysis reveal that providing metformin to TAC/DOCA mice improves diastolic function in the left ventricular (LV) chamber. Muscle mechanics show that metformin lowers passive stiffness of the LV wall muscle. Concomitant with this improvement in diastolic function, metformin-treated TAC/DOCA mice also demonstrate preserved exercise capacity. No metformin effects are seen in sham operated mice. Extraction experiments on skinned ventricular muscle strips show that the metformin-induced reduction of passive stiffness in TAC/DOCA mice is due to an increase in titin compliance. Using phospho-site-specific antibodies, we assay the phosphorylation of titin's PEVK and N2B spring elements. Metformin-treated mice have unaltered PEVK phosphorylation but increased phosphorylation of PKA sites in the N2B element, a change which has previously been shown to lower titin's stiffness. Consistent with this result, experiments with a mouse model deficient in the N2B element reveal that the beneficial effect of metformin on LV chamber and muscle stiffness requires the presence of the N2B element. We conclude that metformin offers therapeutic benefit during HFpEF by lowering titin-based passive stiffness.
Identifiants
pubmed: 30567709
pii: jgp.201812259
doi: 10.1085/jgp.201812259
pmc: PMC6314384
doi:
Substances chimiques
Desoxycorticosterone Acetate
6E0A168OB8
Metformin
9100L32L2N
Protein Kinases
EC 2.7.-
titin protein, mouse
EC 2.7.11.1
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
42-52Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL062881
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL118524
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM084905
Pays : United States
Informations de copyright
© 2018 Slater et al.
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