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J. Biol. Chem., Vol. 280, Issue 8, 6602-6609, February 25, 2005

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Proteolytic N-terminal Truncation of Cardiac Troponin I Enhances Ventricular Diastolic Function^*

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

From the ^¶Section of Molecular Cardiology, Evanston Northwestern Healthcare, Northwestern University Feinberg School of Medicine, Evanston, Illinois 60201, the Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and the ^||Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201

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 -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. Ca²⁺-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 -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.

Received for publication, July 27, 2004 , and in revised form, November 3, 2004.

^* This study was supported in part by National Aeronautics and Space Administration Grant NAG 2-1598, NIAMS, National Institutes of Health (NIH), Grant AR-048816 (to J-P. J.), NHLBI, NIH, Grant HL-56256, and NIA, NIH, Grant AG-16613 (to M. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported in part by NIH Grant T32-HL07653.

^** To whom correspondence should be addressed. Tel.: 847-570-1960; Fax: 847-570-1865; E-mail: jpjin{at}northwestern.edu.

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