Proteolytic N-terminal truncation of cardiac troponin I enhances ventricular diastolic function

John C. Barbato, Qi Quan Huang, M. Moazzem Hossain, Meredith Bond, Jian Ping Jin*

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Besides the core structure conserved in all troponin I isoforms, cardiac troponin I (cTnI) has an N-terminal extension that contains phosphorylation sites for protein kinase A under β-adrenergic regulation. A restricted cleavage of this N-terminal regulatory domain occurs in normal cardiac muscle and is up-regulated during hemodynamic adaptation (Z.-B. Yu, L.-F. Zhang, and J.-P. Jin (2001) J. Biol. Chem. 276, 15753-15760). In the present study, we developed transgenic mice overexpressing the N-terminal truncated cTnI (cTnI-ND) in the heart to examine its biochemical and physiological significance. Ca 2+-activated actomyosin ATPase activity showed that cTnI-ND myofibrils had lower affinity for Ca2+ than controls, similar to the effect of isoproterenol treatment. In vivo and isolated working heart experiments revealed that cTnI-ND hearts had a significantly faster rate of relaxation and lower left ventricular end diastolic pressure compared with controls. The higher baseline relaxation rate of cTnI-ND hearts was at a level similar to that of wild type mouse hearts under 13-adrenergic stimulation. The decrease in cardiac output due to lowered preload was significantly smaller for cTnI-ND hearts compared with controls. These findings indicate that removal of the N-terminal extension of cTnI via restricted proteolysis enhances cardiac function by increasing the rate of myocardial relaxation and lowering left ventricular end diastolic pressure to facilitate ventricular filling, thus resulting in better utilization of the Frank-Starling mechanism.

Original languageEnglish (US)
Pages (from-to)6602-6609
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number8
DOIs
StatePublished - Feb 25 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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