Correcting diastolic dysfunction by Ca2+ desensitizing troponin in a transgenic mouse model of restrictive cardiomyopathy

Yuejin Li, Pierre Yves Jean Charles, Changlong Nan, Jose Renato Pinto, Yingcai Wang, Jingsheng Liang, Gang Wu, Jie Tian, Han Zhong Feng, James D. Potter, J. P. Jin, Xupei Huang

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43 Scopus citations

Abstract

Several cardiac troponin I (cTnI) mutations are associated with restrictive cardiomyopathy (RCM) in humans. We have created transgenic mice (cTnI193His mice) that express the corresponding human RCM R192H mutation. Phenotype of this RCM animal model includes restrictive ventricles, biatrial enlargement and sudden cardiac death, which are similar to those observed in RCM patients carrying the same cTnI mutation. In the present study, we modified the overall cTnI in cardiac muscle by crossing cTnI193His mice with transgenic mice expressing an N-terminal truncated cTnI (cTnI-ND) that enhances relaxation. Protein analyses determined that wild type cTnI was replaced by cTnI-ND in the heart of double transgenic mice (Double TG), which express only cTnI-ND and cTnI R193H in cardiac myocytes. The presence of cTnI-ND effectively rescued the lethal phenotype of RCM mice by reducing the mortality rate. Cardiac function was significantly improved in Double TG mice when measured by echocardiography. The hypersensitivity to Ca2+ and the prolonged relaxation of RCM cTnI193His cardiac myocytes were completely reversed by the presence of cTnI-ND in RCM hearts. The results demonstrate that myofibril hypersensitivity to Ca2+ is a key mechanism that causes impaired relaxation in RCM cTnI mutant hearts and Ca2+ desensitization by cTnI-ND can correct diastolic dysfunction and rescue the RCM phenotypes, suggesting that Ca2+ desensitization in myofibrils is a therapeutic option for treatment of diastolic dysfunction without interventions directed at the systemic β-adrenergic-PKA pathways.

Original languageEnglish
Pages (from-to)402-411
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume49
Issue number3
DOIs
StatePublished - Sep 1 2010

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Keywords

  • Ca desensitization
  • Diastolic dysfunction
  • RCM
  • Transgenic mice
  • Troponin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Li, Y., Charles, P. Y. J., Nan, C., Pinto, J. R., Wang, Y., Liang, J., Wu, G., Tian, J., Feng, H. Z., Potter, J. D., Jin, J. P., & Huang, X. (2010). Correcting diastolic dysfunction by Ca2+ desensitizing troponin in a transgenic mouse model of restrictive cardiomyopathy. Journal of Molecular and Cellular Cardiology, 49(3), 402-411. https://doi.org/10.1016/j.yjmcc.2010.04.017