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; Jonathan P. Davis

doi:10.1038/ncomms10794

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, Jonathan P. Davis

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

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.

Original language	English
Article number	10794
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10794
State	Published - Feb 24 2016

Funding

We thank Dr. Peter Chen (University of Washington) for providing the Adeno-Associated Virus expression vector with internal ribosome entry site-mCherry. We thank Dr Danesh Sopariwala for technical advice regarding collection of VO2max measurements. We thank Ben Canan and Michael Makara for technical advice on ECG measurements and Grace Davis and Jonathan O. Davis for collection of ECG data. We thank Drs. Peter J. Mohler and Muthu Periasamy for critical reading of the manuscript and providing helpful discussions. This effort was supported by NIH grants R01 HL114904 (B.J.B.), R56 HL091986 and R01 HL091986 (J.P.D.), R01HL074045 and R01HL063043 (S.G.), K02 HL094692 (M.T.Z.), R01113084 (P.M.L.J.) and R01 HL115580 (V.V.F.), and National Center for Research Resources Award TL1RR025753 (S.C.L.).P.M.L.J. is also supported by the Fred A. Hitchcock Professorship in Environmental Physiology.

Funders	Funder number
National Institutes of Health (NIH)	R01 HL114904, R01113084, R01 HL115580, R01 HL091986, R01HL063043, R01HL074045
National Heart, Lung, and Blood Institute Family Blood Pressure Program	K02HL094692
National Center for Research Resources	TL1RR025753

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Cite this

Shettigar, V., Zhang, B., Little, S. C., Salhi, H. E., Hansen, B. J., Li, N., Zhang, J., Roof, S. R., Ho, H. T., Brunello, L., Lerch, J. K., Weisleder, N., Fedorov, V. V., Accornero, F., Rafael-Fortney, J. A., Gyorke, S., Janssen, P. M. L., Biesiadecki, B. J., Ziolo, M. T., & Davis, J. P. (2016). Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease. Nature Communications, 7, Article 10794. https://doi.org/10.1038/ncomms10794

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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 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.",

author = "Vikram Shettigar and Bo Zhang and Little, \{Sean C.\} and Salhi, \{Hussam E.\} and Hansen, \{Brian J.\} and Ning Li and Jianchao Zhang and Roof, \{Steve R.\} and Ho, \{Hsiang Ting\} and Lucia Brunello and Lerch, \{Jessica K.\} and Noah Weisleder and Fedorov, \{Vadim V.\} and Federica Accornero and Rafael-Fortney, \{Jill A.\} and Sandor Gyorke and Janssen, \{Paul M.L.\} and Biesiadecki, \{Brandon J.\} and Ziolo, \{Mark T.\} and Davis, \{Jonathan P.\}",

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Shettigar, V, Zhang, B, Little, SC, Salhi, HE, Hansen, BJ, Li, N, Zhang, J, Roof, SR, Ho, HT, Brunello, L, Lerch, JK, Weisleder, N, Fedorov, VV, Accornero, F, Rafael-Fortney, JA, Gyorke, S, Janssen, PML, Biesiadecki, BJ, Ziolo, MT & Davis, JP 2016, 'Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease', Nature Communications, vol. 7, 10794. https://doi.org/10.1038/ncomms10794

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AU - Hansen, Brian J.

AU - Li, Ning

AU - Zhang, Jianchao

AU - Roof, Steve R.

AU - Ho, Hsiang Ting

AU - Brunello, Lucia

AU - Lerch, Jessica K.

AU - Weisleder, Noah

AU - Fedorov, Vadim V.

AU - Accornero, Federica

AU - Rafael-Fortney, Jill A.

AU - Gyorke, Sandor

AU - Janssen, Paul M.L.

AU - Biesiadecki, Brandon J.

AU - Ziolo, Mark T.

AU - Davis, Jonathan P.

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

Abstract

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