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Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.


ABSTRACT: Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.

SUBMITTER: Malik FI 

PROVIDER: S-EPMC4090309 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.

Malik Fady I FI   Hartman James J JJ   Elias Kathleen A KA   Morgan Bradley P BP   Rodriguez Hector H   Brejc Katjusa K   Anderson Robert L RL   Sueoka Sandra H SH   Lee Kenneth H KH   Finer Jeffrey T JT   Sakowicz Roman R   Baliga Ramesh R   Cox David R DR   Garard Marc M   Godinez Guillermo G   Kawas Raja R   Kraynack Erica E   Lenzi David D   Lu Pu Ping PP   Muci Alexander A   Niu Congrong C   Qian Xiangping X   Pierce Daniel W DW   Pokrovskii Maria M   Suehiro Ion I   Sylvester Sheila S   Tochimoto Todd T   Valdez Corey C   Wang Wenyue W   Katori Tatsuo T   Kass David A DA   Shen You-Tang YT   Vatner Stephen F SF   Morgans David J DJ  

Science (New York, N.Y.) 20110301 6023


Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the  ...[more]

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