title: Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease.
abstract: Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Here we develop a protein engineering approach to directly tune in vivo cardiac contractility by tailoring the ability of the heart to respond to the Ca(2+) signal. Promisingly, our smartly formulated Ca(2+)-sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. In a myocardial infarction (MI) model of heart failure, expression of TnC L48Q before the MI preserves cardiac function and performance. Moreover, expression of TnC L48Q after the MI therapeutically enhances cardiac function and performance, without compromising survival. We demonstrate engineering TnC can specifically and precisely modulate cardiac contractility that when combined with gene therapy can be employed as a therapeutic strategy for heart disease.
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Shettigar
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Bristol-Myers Squibb, Department of Discovery Biology, Wallingford, Connecticut 06492, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Little
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Hussam E
authors.initials: HE
authors.lastname: Salhi
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hansen
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Jianchao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Q-Test Labs, Columbus, Ohio 43235, USA.
authors.forename: Steve R
authors.initials: SR
authors.lastname: Roof
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Ho
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Brunello
authors.affiliation: Center for Brain and Spinal Cord Repair, Department of Neuroscience, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Lerch
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Weisleder
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Fedorov
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Accornero
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rafael-Fortney
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Sandor
authors.initials: S
authors.lastname: Gyorke
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Biesiadecki
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Ziolo
authors.affiliation: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, Columbus, Ohio 43210, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Davis
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004562:Electrocardiography; D005080:Exercise Test; D017079:Exercise Tolerance; D015316:Genetic Therapy; D005822:Genetic Vectors; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D061848:Optical Imaging; D015202:Protein Engineering; D011817:Rabbits; D019209:Troponin C / Q000235:genetics* / Q000378:metabolism; D014463:Ultrasonography; D016276:Ventricular Function
chemical_list: D019209:Troponin C; D002118:Calcium