Abstract
Cardiac TnI (cTnI) has an N-terminal extension containing two protein kinase A (PKA) phosphorylation sites, Ser23/24, and its removal by restrictive proteolysis in cardiac adaptation improves myocardial relaxation. Through transgenic expression of the N-terminal truncated cTnI (cTnI-ND) in the heart of endogenous cTnI knockout mice, we studied the function of cardiac muscle containing only cTnI-ND. The pure cTnI-ND hearts showed no hypertrophy or dilation with normal baseline function as compared to wild type controls (WT), confirming the non-destructive nature of cTnI-ND. Echocardiography found increased left ventricular end diastolic dimension in cTnI-ND hearts as compared to WT, implying increased relaxation and compliance in vivo. A series of preloads was tested in ex vivo working hearts for the effects of cTnI-ND on Frank-Starling response. cTnI-ND hearts showed responses to 5-10 mmHg preloads similar to that of WT. When preload was increased from 10 to 20 mmHg, cTnI-ND hearts exhibited better maintained left ventricular relaxation velocity, lower left ventricular end diastolic pressure and larger stroke volume responses than that of WT hearts. 10 nM isoproterenol further increased the positive effects of cTnI-ND on the responses of cardiac function to preloads, indicating that cTnI-ND enhances Frank-Starling relationship in the absence of direct effect of PKA phosphorylation at Ser23/24. Slack sarcomere length in isolated cardiomyocytes and the optimal sarcomere length for maximum tension development in intact left ventricular papillary muscle from cTnI-ND mice were similar to that of WT, suggesting that cTnI-ND extends the range of Frank-Starling response to high preloads by enhancing contractility independent of further increases in sarcomere length. The results demonstrated that the removal of cTnI N-terminal extension by restrictive proteolysis provides a novel posttranslational modification to utilize Frank-Starling mechanism in cardiac adaptation to physiological and pathological stresses.
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