Single histidine-substituted cardiac troponin I confers protection from age-related systolic and diastolic dysfunction

Palpant, Nathan J., Day, Sharlene M., Herron, Todd J., Converso, Kimber L. and Metzger, Joseph M. (2008) Single histidine-substituted cardiac troponin I confers protection from age-related systolic and diastolic dysfunction. Cardiovascular Research, 80 2: 209-218. doi:10.1093/cvr/cvn198


Author Palpant, Nathan J.
Day, Sharlene M.
Herron, Todd J.
Converso, Kimber L.
Metzger, Joseph M.
Title Single histidine-substituted cardiac troponin I confers protection from age-related systolic and diastolic dysfunction
Journal name Cardiovascular Research   Check publisher's open access policy
ISSN 0008-6363
1755-3245
Publication date 2008-11-01
Year available 2008
Sub-type Article (original research)
DOI 10.1093/cvr/cvn198
Open Access Status Not yet assessed
Volume 80
Issue 2
Start page 209
End page 218
Total pages 10
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Formatted abstract
Aims: Contractile dysfunction associated with myocardial ischaemia is a significant cause of morbidity and mortality in the elderly. Strategies to protect the aged heart from ischaemia-mediated pump failure are needed. We hypothesized that troponin I-mediated augmentation of myofilament calcium sensitivity would protect cardiac function in aged mice.

Methods and results: To address this, we investigated transgenic (Tg) mice expressing a histidine-substituted form of adult cardiac troponin I (cTnI A164H), which increases myofilament calcium sensitivity in a pH-dependent manner. Serial echocardiography revealed that Tg hearts showed significantly improved systolic function at 4 months, which was sustained for 2 years based on ejection fraction and velocity of circumferential fibre shortening. Age-related diastolic dysfunction was also attenuated in Tg mice as assessed by Doppler measurements of the mitral valve inflow and lateral annulus Doppler tissue imaging. During acute hypoxia, cardiac contractility significantly improved in aged Tg mice made evident by increased stroke volume, end systolic pressure, and +dP/dt compared with non-transgenic mice.

Conclusion: This study shows that increasing myofilament function by means of a pH-responsive histidine button engineered into cTnI results in enhanced baseline heart function in Tg mice over their lifetime, and during acute hypoxia improves survival in aged mice by maintaining cardiac contractility.
Keyword Ageing
Cardiac function
Hypoxia
Troponin I
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID RO1 HL 059301
0715632Z to N.P
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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