دورية أكاديمية
أعرض في EDS

A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice.

التفاصيل البيبلوغرافية
العنوان: A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice.
المؤلفون: Green EM; MyoKardia, South San Francisco, CA 94080, USA., Wakimoto H; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Anderson RL; MyoKardia, South San Francisco, CA 94080, USA., Evanchik MJ; MyoKardia, South San Francisco, CA 94080, USA., Gorham JM; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Harrison BC; Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA., Henze M; MyoKardia, South San Francisco, CA 94080, USA., Kawas R; MyoKardia, South San Francisco, CA 94080, USA., Oslob JD; MyoKardia, South San Francisco, CA 94080, USA., Rodriguez HM; MyoKardia, South San Francisco, CA 94080, USA., Song Y; MyoKardia, South San Francisco, CA 94080, USA., Wan W; Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA., Leinwand LA; Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, CO 80309, USA., Spudich JA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA., McDowell RS; MyoKardia, South San Francisco, CA 94080, USA. cseidman@genetics.harvard.edu rmcdowell@myokardia.com., Seidman JG; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Seidman CE; 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.
المصدر: Science (New York, N.Y.) [Science] 2016 Feb 05; Vol. 351 (6273), pp. 617-21.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE
أسماء مطبوعة: Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-
مواضيع طبية MeSH: Adenosine Triphosphatases/*antagonists & inhibitors , Benzylamines/*administration & dosage , Cardiac Myosins/*antagonists & inhibitors , Cardiomyopathy, Hypertrophic, Familial/*drug therapy , Myocardial Contraction/*drug effects , Myosin Heavy Chains/*antagonists & inhibitors , Sarcomeres/*drug effects , Uracil/*analogs & derivatives, Animals ; Benzylamines/chemistry ; Cardiac Myosins/genetics ; Cardiomyopathy, Hypertrophic, Familial/pathology ; Cardiomyopathy, Hypertrophic, Familial/physiopathology ; Cells, Cultured ; Disease Models, Animal ; Fibrosis ; Heart Ventricles/drug effects ; Heart Ventricles/pathology ; Heterozygote ; Humans ; Male ; Mice ; Mice, Inbred Strains ; Mutation ; Myocardium/pathology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/pathology ; Myosin Heavy Chains/genetics ; Rats ; Uracil/administration & dosage ; Uracil/chemistry
مستخلص: 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.
(Copyright © 2016, American Association for the Advancement of Science.)
التعليقات: Comment in: Science. 2016 Feb 5;351(6273):556-7. (PMID: 26912685)
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معلومات مُعتمدة: R01 GM033289 United States GM NIGMS NIH HHS; 5K01AR055676 United States AR NIAMS NIH HHS; R01 HL117138 United States HL NHLBI NIH HHS; United States Howard Hughes Medical Institute; R01 HL084553 United States HL NHLBI NIH HHS; K01 AR055676 United States AR NIAMS NIH HHS
المشرفين على المادة: 0 (Benzylamines)
0 (MYK-461)
56HH86ZVCT (Uracil)
EC 3.6.1.- (Adenosine Triphosphatases)
EC 3.6.1.- (Cardiac Myosins)
EC 3.6.4.1 (Myosin Heavy Chains)
تواريخ الأحداث: Date Created: 20160226 Date Completed: 20160322 Latest Revision: 20220316
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC4784435
DOI: 10.1126/science.aad3456
PMID: 26912705
قاعدة البيانات: MEDLINE
الوصف
تدمد:1095-9203
DOI:10.1126/science.aad3456