Extracellular stiffness induces contractile dysfunction in adult cardiomyocytes via cell-autonomous and microtubule-dependent mechanisms.

Autor: Vite A; Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Smillow TRC 11-101, Philadelphia, PA, 19104, USA., Caporizzo MA; Department of Molecular Physiology and Biophysics, University of Vermont's Larner College of Medicine, Burlington, VT, USA., Corbin EA; Departments of Biomedical Engineering and Materials Science, University of Delaware, Newark, DE, USA., Brandimarto J; Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Smillow TRC 11-101, Philadelphia, PA, 19104, USA., McAfee Q; Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Smillow TRC 11-101, Philadelphia, PA, 19104, USA., Livingston CE; Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Smillow TRC 11-101, Philadelphia, PA, 19104, USA., Prosser BL; Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Margulies KB; Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Smillow TRC 11-101, Philadelphia, PA, 19104, USA. kenb@pennmedicine.upenn.edu.; Department of Physiology and Pennsylvania Muscle Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. kenb@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Basic research in cardiology [Basic Res Cardiol] 2022 Aug 25; Vol. 117 (1), pp. 41. Date of Electronic Publication: 2022 Aug 25.
DOI: 10.1007/s00395-022-00952-5
Abstrakt: The mechanical environment of the myocardium has a potent effect on cardiomyocyte form and function, yet an understanding of the cardiomyocyte responses to extracellular stiffening remains incomplete. We therefore employed a cell culture substrate with tunable stiffness to define the cardiomyocyte responses to clinically relevant stiffness increments in the absence of cell-cell interactions. When cultured on substrates magnetically actuated to mimic the stiffness of diseased myocardium, isolated rat adult cardiomyocytes exhibited a time-dependent reduction of sarcomere shortening, characterized by slowed contraction and relaxation velocity, and alterations of the calcium transient. Cardiomyocytes cultured on stiff substrates developed increases in viscoelasticity and microtubule detyrosination in association with early increases in the α-tubulin detyrosinating enzyme vasohibin-2 (Vash2). We found that knockdown of Vash2 was sufficient to preserve contractile performance as well as calcium transient properties in the presence of extracellular substrate stiffening. Orthogonal prevention of detyrosination by overexpression of tubulin tyrosine ligase (TTL) was also able to preserve contractility and calcium homeostasis. These data demonstrate that a pathologic increment of extracellular stiffness induces early, cell-autonomous remodeling of adult cardiomyocytes that is dependent on detyrosination of α-tubulin.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)
Databáze: MEDLINE
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