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A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban
- Source :
- European journal of pharmacology. 814
- Publication Year :
- 2017
-
Abstract
- The cardiac sarco/endoplasmic reticulum Ca2+-dependent ATPase 2a (SERCA2a) plays a central role in Ca2+ handling within cardiomyocytes and is negatively regulated by phospholamban (PLN), a sarcoplasmic reticulum (SR) membrane protein. The activation of SERCA2a, which has been reported to improve cardiac dysfunction in heart failure, is a potential therapeutic approach for heart failure. Therefore, we developed a novel small molecule, compound A and characterized it both in vitro and in vivo. Compound A activated the Ca2+-dependent ATPase activity of cardiac SR vesicles but not that of skeletal muscle SR vesicles that lack PLN. The surface plasmon resonance assay revealed a direct interaction between compound A and PLN, suggesting that the binding of compound A to PLN attenuates its inhibition of SERCA2a, resulting in SERCA2a activation. This was substantiated by inhibition of the compound A-mediated increase in Ca2+ levels within the SR of HL-1 cells by thapsigargin, a SERCA inhibitor. Compound A also increased the Ca2+ transients and contraction and relaxation of isolated adult rat cardiomyocytes. In isolated perfused rat hearts, the compound A enhanced systolic and diastolic functions. Further, an infusion of compound A (30mg/kg, i.v. bolus followed by 2mg/kg/min, i.v. infusion) significantly enhanced the diastolic function in anesthetized normal rats. These results indicate that compound A is a novel SERCA2a activator, which attenuates PLN inhibition and enhances the systolic and diastolic functions of the heart in vitro and in vivo. Therefore, compound A might be a novel therapeutic lead for heart failure.
- Subjects :
- 0301 basic medicine
Male
Sarcomeres
medicine.medical_specialty
Contraction (grammar)
Thapsigargin
SERCA
Pyridones
ATPase
030204 cardiovascular system & hematology
Cell Line
Sarcoplasmic Reticulum Calcium-Transporting ATPases
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
In vivo
Internal medicine
medicine
Animals
Enzyme Inhibitors
Rats, Wistar
Pharmacology
biology
Endoplasmic reticulum
Calcium-Binding Proteins
Hemodynamics
Skeletal muscle
Phospholamban
Rats
Enzyme Activation
030104 developmental biology
Endocrinology
medicine.anatomical_structure
chemistry
cardiovascular system
biology.protein
Calcium
Subjects
Details
- ISSN :
- 18790712
- Volume :
- 814
- Database :
- OpenAIRE
- Journal :
- European journal of pharmacology
- Accession number :
- edsair.doi.dedup.....a6437f184106b65cd94e042af0fbffce