A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice
By Eric M. Green, H. Wakimoto, R. Anderson, M. Evanchik, J. Gorham, B. Harrison, M. Henze, Raja Kawas, J. Oslob, Hector M. Rodriguez and 7 more. Science, 2016
633 citations recorded by the source corpus.
Powering down yields a healthier heart In hypertrophic cardiomyopathy (HCM), the heart muscle enlarges and becomes progressively less efficient at pumping blood. HCM can be caused by mutations in components of the sarcomere (the heart's contractile unit), most notably myosin. Hypercontractility is among the earliest heart disturbances seen in mice carrying these myosin mutations, implying that the mutations inflict their damage by increasing myosin's power production. Green et al. identified a small molecule that binds to myosin and inhibits its activity (see the Perspective by Warshaw). When orally administered to young mice, the molecule prevented the development of several hallmark features of HCM without adversely affecting skeletal muscle. Science, this issue p. 617; see also p. 556 A small molecule that reduces cardiac muscle contraction prevents a certain type of heart disease in mice. [Also see Perspective by Warshaw] 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.
Subfields: Cardiology and Cardiovascular Medicine, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/1769bb8ebbf8f90c0a916e493a475766ad5ab41c
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In Cardiology and Cardiovascular Medicine
In Molecular Biology
Citations in the corpus
- Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy. (2017, methodology): “The modifier variants, unlike the causal mutations, are neither necessary nor sufficient to cause HCM.”