Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease

Vikram Shettigar, Bo Zhang, Sean C. Little, Hussam E. Salhi, Brian J. Hansen, Ning Li, Jianchao Zhang, Steve R. Roof, Hsiang-Ting Ho, Lucia Brunello, Jessica K. Lerch, Noah Weisleder, Vadim V. Fedorov, Federica Accornero, Jill A. Rafael-Fortney, Sandor Gyorke, Paul M. L. Janssen, Brandon J. Biesiadecki, Mark T. Ziolo () and Jonathan P. Davis ()
Additional contact information
Vikram Shettigar: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Bo Zhang: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Sean C. Little: Bristol-Myers Squibb
Hussam E. Salhi: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Brian J. Hansen: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Ning Li: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Jianchao Zhang: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Steve R. Roof: Q-Test Labs
Hsiang-Ting Ho: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Lucia Brunello: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Jessica K. Lerch: Center for Brain and Spinal Cord Repair, The Ohio State University College of Medicine
Noah Weisleder: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Vadim V. Fedorov: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Federica Accornero: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Jill A. Rafael-Fortney: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Sandor Gyorke: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Paul M. L. Janssen: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Brandon J. Biesiadecki: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Mark T. Ziolo: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology
Jonathan P. Davis: Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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 Ca2+ signal. Promisingly, our smartly formulated Ca2+-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.

Date: 2016
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DOI: 10.1038/ncomms10794

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