1. A pyridone derivative activates SERCA2a by attenuating the inhibitory effect of phospholamban
- Author
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Hideyuki Igawa, Hiroki Takahagi, Hisato Yamamoto, Manami Kaneko, Masakuni Noda, Shuji Fujiwara, Tomoyuki Nishimoto, Yusuke Kamada, Shizuo Kasai, Toshiki Tanaka, Makoto Inui, Hiroki Sakai, and Syunsuke Yamamoto
- 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 - 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.
- Published
- 2017