Cardiac Myosin Activation: A Potential Therapeutic Approach for Systolic Heart Failure
| Autor: | Katjuša Brejc, Jeffrey T. Finer, Maria Pokrovskii, David R. Cox, Daniel W. Pierce, Marc Garard, Ramesh Baliga, Congrong Niu, Todd Tochimoto, Kathleen A. Elias, Guillermo Godinez, Stephen F. Vatner, You Tang Shen, Roman Sakowicz, Bradley P. Morgan, Sandra H. Sueoka, Pu Ping Lu, Fady I. Malik, Tatsuo Katori, Alexander Muci, David Lenzi, David J. Morgans, Corey Valdez, Sheila Sylvester, Kenneth Lee, Xiangping Qian, Ion Suehiro, Erica Kraynack, Raja Kawas, David A. Kass, James J. Hartman, Hector P. Rodriguez, Robert L. Anderson, Wenyue Wang |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Cardiac function curve Cardiac output medicine.medical_specialty Protein Conformation macromolecular substances Biology Ventricular Function Left Phosphates Rats Sprague-Dawley Contractility Adenosine Triphosphate Dogs Cardiac Myosins Allosteric Regulation Internal medicine Myosin medicine Animals Protein Isoforms Urea Myocytes Cardiac Cardiac Output Adenosine Triphosphatases Binding Sites Multidisciplinary Isoproterenol Adrenergic beta-Agonists medicine.disease Actin cytoskeleton Myocardial Contraction Actins Rats Actin Cytoskeleton Omecamtiv mecarbil Endocrinology Heart failure Cardiology Calcium Female Heart Failure Systolic Protein Binding |
| Zdroj: | Science. 331:1439-1443 |
| ISSN: | 1095-9203 0036-8075 |
| DOI: | 10.1126/science.1200113 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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