Cardiovascular research · 2018
Biomechanical defects and rescue of cardiomyocytes expressing pathologic nuclear lamins.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Laurini Erik, Martinelli Valentina, Lanzicher Thomas, Puzzi Luca, Borin Daniele, Chen Suet Nee, Long Carlin S, Lee Patrice, Mestroni Luisa, Taylor Matthew R G, Sbaizero Orfeo, Pricl Sabrina
Аннотация
AIMS: Given the clinical impact of LMNA cardiomyopathies, understanding lamin function will fulfill a clinical need and will lead to advancement in the treatment of heart failure. A multidisciplinary approach combining cell biology, atomic force microscopy (AFM), and molecular modeling was used to analyse the biomechanical properties of human lamin A/C gene (LMNA) mutations (E161K, D192G, N195K) using an in vitro neonatal rat ventricular myocyte model.
METHODS AND RESULTS: The severity of biomechanical defects due to the three LMNA mutations correlated with the severity of the clinical phenotype. AFM and molecular modeling identified distinctive biomechanical and structural changes, with increasing severity from E161K to N195K and D192G, respectively. Additionally, the biomechanical defects were rescued with a p38 MAPK inhibitor.
CONCLUSIONS: AFM and molecular modeling were able to quantify distinct biomechanical and structural defects in LMNA mutations E161K, D192G, and N195K and correlate the defects with clinical phenotypic severity. Improvements in cellular biomechanical phenotype was demonstrated and may represent a mechanism of action for p38 MAPK inhibition therapy that is now being used in human clinical trials to treat laminopathies.
METHODS AND RESULTS: The severity of biomechanical defects due to the three LMNA mutations correlated with the severity of the clinical phenotype. AFM and molecular modeling identified distinctive biomechanical and structural changes, with increasing severity from E161K to N195K and D192G, respectively. Additionally, the biomechanical defects were rescued with a p38 MAPK inhibitor.
CONCLUSIONS: AFM and molecular modeling were able to quantify distinct biomechanical and structural defects in LMNA mutations E161K, D192G, and N195K and correlate the defects with clinical phenotypic severity. Improvements in cellular biomechanical phenotype was demonstrated and may represent a mechanism of action for p38 MAPK inhibition therapy that is now being used in human clinical trials to treat laminopathies.
Предметные рубрики MeSH
AnimalsAnimals, NewbornBiomechanical PhenomenaCardiomyopathiesCells, CulturedElastic ModulusFluorescent Antibody TechniqueGenetic Predisposition to DiseaseHumansLamin Type AMicroscopy, Atomic ForceMolecular Dynamics SimulationMutationMyocardial ContractionMyocytes, CardiacPhenotypeProtein Conformation, alpha-HelicalProtein Kinase InhibitorsRatsStructure-Activity Relationshipp38 Mitogen-Activated Protein Kinases