title: Proteolytic N-terminal truncation of cardiac troponin I enhances ventricular diastolic function.
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 beta-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 Ca(2+) 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 beta-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.
authors.affiliation: Section of Molecular Cardiology, Evanston Northwestern Healthcare, Northwestern University Feinberg School of Medicine, Evanston, Illinois 60201, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Barbato
authors.forename: Qi-Quan
authors.initials: QQ
authors.lastname: Huang
authors.forename: M Moazzem
authors.initials: MM
authors.lastname: Hossain
authors.forename: Meredith
authors.initials: M
authors.lastname: Bond
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Jin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002302:Cardiac Output; D003971:Diastole; D006321:Heart; D051379:Mice; D008822:Mice, Transgenic; D009126:Muscle Relaxation; D010447:Peptide Hydrolases / Q000378:metabolism*; D017384:Sequence Deletion; D019076:Transgenes; D019210:Troponin I / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016276:Ventricular Function
chemical_list: D019210:Troponin I; D010447:Peptide Hydrolases; D002118:Calcium