Sarcomere neutralization in inherited cardiomyopathy: small-molecule proof-of-concept to correct hyper-Ca2+-sensitive myofilaments.
Am J Physiol Heart Circ Physiol
; 311(1): H36-43, 2016 07 01.
Article
de En
| MEDLINE
| ID: mdl-27199134
ABSTRACT
The sarcomere is the functional unit of the heart. Alterations in sarcomere activation lead to disease states such as hypertrophic and restrictive cardiomyopathy (HCM/RCM). Mutations in many of the sarcomeric genes are causal for HCM/RCM. In most cases, these mutations result in increased Ca(2+) sensitivity of the sarcomere, giving rise to altered systolic and diastolic function. There is emerging evidence that small-molecule sarcomere neutralization is a potential therapeutic strategy for HCM/RCM. To pursue proof-of-concept, W7 was used here because of its well-known Ca(2+) desensitizer biochemical effects at the level of cardiac troponin C. Acute treatment of adult cardiac myocytes with W7 caused a dose-dependent (1-10 µM) decrease in contractility in a Ca(2+)-independent manner. Alkalosis was used as an in vitro experimental model of acquired heightened Ca(2+) sensitivity, resulting in increased live cell contractility and decreased baseline sarcomere length, which were rapidly corrected with W7. As an inherited cardiomyopathy model, R193H cardiac troponin I (cTnI) transgenic myocytes showed significant decreased baseline sarcomere length and slowed relaxation that were rapidly and dose-dependently corrected by W7. Langendorff whole heart pacing stress showed that R193H cTnI transgenic hearts had elevated end-diastolic pressures at all pacing frequencies compared with hearts from nontransgenic mice. Acute treatment with W7 rapidly restored end-diastolic pressures to normal values in R193H cTnI hearts, supporting a sarcomere intrinsic mechanism of dysfunction. The known off-target effects of W7 notwithstanding, these results provide further proof-of-concept that small-molecule-based sarcomere neutralization is a potential approach to remediate hyper-Ca(2+)-sensitive sarcomere function.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Sarcomères
/
Sulfonamides
/
Signalisation calcique
/
Myocytes cardiaques
/
Antienzymes
/
Contraction myocardique
/
Cardiomyopathies
Type d'étude:
Diagnostic_studies
Limites:
Animals
Langue:
En
Journal:
Am J Physiol Heart Circ Physiol
Sujet du journal:
CARDIOLOGIA
/
FISIOLOGIA
Année:
2016
Type de document:
Article