Cardiac myosin activation: A potential therapeutic approach for systolic heart failure

Fady I. Malik, James J. Hartman, Kathleen A. Elias, Bradley P. Morgan, Hector Rodriguez, Katjuša Brejc, Robert L. Anderson, Sandra H. Sueoka, Kenneth H. Lee, Jeffrey T. Finer, Roman Sakowicz, Ramesh Baliga, David R. Cox, Marc Garard, Guillermo Godinez, Raja Kawas, Erica Kraynack, David Lenzi, Pu Ping Lu, Alexander MuciCongrong Niu, Xiangping Qian, Daniel W. Pierce, Maria Pokrovskii, Ion Suehiro, Sheila Sylvester, Todd Tochimoto, Corey Valdez, Wenyue Wang, Tatsuo Katori, David A. Kass, You Tang Shen, Stephen F. Vatner, David J. Morgans

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1439-1443
Number of pages5
JournalScience
Volume331
Issue number6023
DOIs
StatePublished - Mar 18 2011

ASJC Scopus subject areas

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    Malik, F. I., Hartman, J. J., Elias, K. A., Morgan, B. P., Rodriguez, H., Brejc, K., Anderson, R. L., Sueoka, S. H., Lee, K. H., Finer, J. T., Sakowicz, R., Baliga, R., Cox, D. R., Garard, M., Godinez, G., Kawas, R., Kraynack, E., Lenzi, D., Lu, P. P., ... Morgans, D. J. (2011). Cardiac myosin activation: A potential therapeutic approach for systolic heart failure. Science, 331(6023), 1439-1443. https://doi.org/10.1126/science.1200113