Removal of the N-terminal Extension of Cardiac Troponin I as a Functional Compensation for Impaired Myocardial β-Adrenergic Signaling

摘要

Although β-adrenergic stimuli are essential for myocardial contractility, β-blockers have a proven beneficial effect on the treatment of heart failure, but the mechanism is not fully understood. The stimulatory G protein α-subunit (Gsα) couples the β-adrenoreceptor to adenylyl cyclase and the intracellular cAMP response. In a mouse model of conditional Gsα deficiency in the cardiac muscle (Gsα-DF), we demonstrated heart failure phenotypes accompanied by increases in the level of a truncated cardiac troponin I (cTnI-ND) from restricted removal of the cTnI-specific N-terminal extension. To investigate the functional significance of the increase of cTnI-ND in Gsα-DF cardiac muscle, we generated double transgenic mice to overexpress cTnI-ND in Gsα-DF hearts. The overexpression of cTnI-ND in Gsα-DF failing hearts increased relaxation velocity and left ventricular end diastolic volume to produce higher left ventricle maximum pressure and stroke volume. Supporting the hypothesis that up-regulation of cTnI-ND is a compensatory rather than a destructive myocardial response to impaired β-adrenergic signaling, the aberrant expression of β-myosin heavy chain in adult Gsα-DF but not control mouse hearts was reversed by cTnI overexpression. These data indicate that the up-regulation of cTnI-ND may partially compensate for the cardiac inefficiency in impaired β-adrenergic signaling.