title: Novel role for vinculin in ventricular myocyte mechanics and dysfunction.
abstract: Vinculin (Vcl) plays a key structural role in ventricular myocytes that, when disrupted, can lead to contractile dysfunction and dilated cardiomyopathy. To investigate the role of Vcl in myocyte and myocardial function, cardiomyocyte-specific Vcl knockout mice (cVclKO) and littermate control wild-type mice were studied with transmission electron microscopy (TEM) and in vivo magnetic resonance imaging (MRI) tagging before the onset of global ventricular dysfunction. MRI revealed significantly decreased systolic strains transverse to the myofiber axis in vivo, but no changes along the muscle fibers or in fiber tension in papillary muscles from heterozygous global Vcl null mice. Myofilament lattice spacing from TEM was significantly greater in cVclKO versus wild-type hearts fixed in the unloaded state. AFM in Vcl heterozygous null mouse myocytes showed a significant decrease in membrane cortical stiffness. A multiscale computational model of ventricular mechanics incorporating cross-bridge geometry and lattice mechanics showed that increased transverse systolic stiffness due to increased lattice spacing may explain the systolic wall strains associated with Vcl deficiency, before the onset of ventricular dysfunction. Loss of cardiac myocyte Vcl may decrease systolic transverse strains in vivo by decreasing membrane cortical tension, which decreases transverse compression of the lattice thereby increasing interfilament spacing and stress transverse to the myofibers.
authors.affiliation: Department of Bioengineering, University of California-San Diego, La Jolla, California, USA.
authors.forename: Jared R
authors.initials: JR
authors.lastname: Tangney
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Chuang
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Janssen
authors.forename: Adarsh
authors.initials: A
authors.lastname: Krishnamurthy
authors.forename: Peter
authors.initials: P
authors.lastname: Liao
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Meininger
authors.forename: Mariappan
authors.initials: M
authors.lastname: Muthuchamy
authors.forename: Alice
authors.initials: A
authors.lastname: Zemljic-Harpf
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ross
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Frank
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Omens
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D055786:Gene Knockout Techniques; D006352:Heart Ventricles / Q000166:cytology* / Q000473:pathology / Q000503:physiopathology*; D055595:Mechanical Phenomena; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology; D013314:Stress, Mechanical; D018754:Ventricular Dysfunction / Q000378:metabolism* / Q000473:pathology; D016596:Vinculin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016596:Vinculin
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