Publication Date:
2016-02-26
Description:
Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Green, Eric M -- Wakimoto, Hiroko -- Anderson, Robert L -- Evanchik, Marc J -- Gorham, Joshua M -- Harrison, Brooke C -- Henze, Marcus -- Kawas, Raja -- Oslob, Johan D -- Rodriguez, Hector M -- Song, Yonghong -- Wan, William -- Leinwand, Leslie A -- Spudich, James A -- McDowell, Robert S -- Seidman, J G -- Seidman, Christine E -- 5K01AR055676/AR/NIAMS NIH HHS/ -- R01 GM033289/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Feb 5;351(6273):617-21. doi: 10.1126/science.aad3456.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MyoKardia, South San Francisco, CA 94080, USA. ; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA. ; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA. ; MyoKardia, South San Francisco, CA 94080, USA. cseidman@genetics.harvard.edu rmcdowell@myokardia.com. ; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. cseidman@genetics.harvard.edu rmcdowell@myokardia.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912705" target="_blank"〉PubMed〈/a〉
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
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Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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