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

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. 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. The β-adrenoreceptor (β-AR) 3The abbreviations used are: β-ARβ-adrenoceptorGsαG protein α subunitGsα-DFstimulatory G protein α subunit deficiencycTnIcardiac troponin IcTnI-NDN-terminal truncated cardiac troponin IMHCmyosin heavy chainPKAprotein kinase AP-Vpressure-volumeMCKmuscle creatine kinase. 3The abbreviations used are: β-ARβ-adrenoceptorGsαG protein α subunitGsα-DFstimulatory G protein α subunit deficiencycTnIcardiac troponin IcTnI-NDN-terminal truncated cardiac troponin IMHCmyosin heavy chainPKAprotein kinase AP-Vpressure-volumeMCKmuscle creatine kinase. signaling pathway plays an important role in the regulation of heart function (1Bristow M.R. Hershberger R.E. Port J.D. Gilbert E.M. Sandoval A. Rasmussen R. Cates A.E. Feldman A.M. Circulation. 1990; 82: I12-I25Crossref PubMed Scopus (42) Google Scholar, 2Homcy C.J. Vatner S.F. 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Circ. Res. 1989; 64: 104-111Crossref PubMed Scopus (115) Google Scholar), and myofilament proteins (cardiac troponin I (cTnI) (7Kranias E.G. Solaro R.J. Nature. 1982; 298: 182-184Crossref PubMed Scopus (177) Google Scholar) and myosin-binding protein C (8Hartzell H.C. Glass D.B. J. Biol. Chem. 1984; 259: 15587-15596Abstract Full Text PDF PubMed Google Scholar)). β-adrenoceptor G protein α subunit stimulatory G protein α subunit deficiency cardiac troponin I N-terminal truncated cardiac troponin I myosin heavy chain protein kinase A pressure-volume muscle creatine kinase. β-adrenoceptor G protein α subunit stimulatory G protein α subunit deficiency cardiac troponin I N-terminal truncated cardiac troponin I myosin heavy chain protein kinase A pressure-volume muscle creatine kinase. In heart failure patients, the level of plasma norepinephrine is enhanced, resulting from activation of sympathetic nervous system, which induces chronic stimulation of cardiac β-adrenergic receptors (9Cohn J.N. Levine T.B. Olivari M.T. Garberg V. Lura D. Francis G.S. Simon A.B. Rector T. N. Engl. J. Med. 1984; 311: 819-823Crossref PubMed Scopus (2775) Google Scholar). Although acute β-stimulation enhances cardiac function to adapt to systemic needs, chronic stimulation of the β1-adrenergic receptor is detrimental and contributes to cardiomyocyte hypertrophy, cell death, and progression of heart failure (10Bristow M.R. Circulation. 2000; 101: 558-569Crossref PubMed Scopus (936) Google Scholar, 11Engelhardt S. Heart Fail. Clin. 2005; 1: 183-191Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 12Lohse M.J. Engelhardt S. Eschenhagen T. Circ. Res. 2003; 93: 896-906Crossref PubMed Scopus (602) Google Scholar). Transgenic mice overexpressing β1-adrenoreceptor (13Engelhardt S. Hein L. Wiesmann F. Lohse M.J. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7059-7064Crossref PubMed Scopus (655) Google Scholar) or the Gs subunit α (Gsα) (14Vatner S.F. Vatner D.E. Homcy C.J. Circ. Res. 2000; 86: 502-506Crossref PubMed Scopus (53) Google Scholar) in the heart developed heart failure with increased level of apoptosis and fibrotic degeneration similar to that observed in dilated cardiomyopathy in humans. Overexpression of the catalytic subunit of PKA also produced cardiomyocyte hypertrophy, fibrosis, and a progressive decline in cardiac function, resulting in heart failure (15Antos C.L. Frey N. Marx S.O. Reiken S. Gaburjakova M. Richardson J.A. Marks A.R. Olson E.N. Circ. Res. 2001; 89: 997-1004Crossref PubMed Scopus (223) Google Scholar). On the other hand, failing hearts respond to the chronically elevated norepinephrine concentrations by desensitizing their response to β-adrenergic stimulation (11Engelhardt S. Heart Fail. Clin. 2005; 1: 183-191Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 16Bristow M.R. Ginsburg R. Minobe W. Cubicciotti R.S. Sageman W.S. Lurie K. Billingham M.E. Harrison D.C. Stinson E.B. N. Engl. J. Med. 1982; 307: 205-211Crossref PubMed Scopus (1936) Google Scholar). Cardiac TnI is the inhibitory subunit of the troponin complex and plays an essential role in Ca2+ regulation of cardiac muscle contraction. Cardiac TnI is a substrate of PKA and is phosphorylated upon β-adrenergic stimulation (7Kranias E.G. Solaro R.J. Nature. 1982; 298: 182-184Crossref PubMed Scopus (177) Google Scholar). The PKA phosphorylation sites are two adjacent serine residues, Ser23/Ser24 (rat/mouse residue numbers), located in the cardiac specific N-terminal extension of cTnI. β-Adrenergic stimulated phosphorylation of cTnI Ser23/Ser24 reduces myofilament Ca2+ sensitivity (7Kranias E.G. Solaro R.J. Nature. 1982; 298: 182-184Crossref PubMed Scopus (177) Google Scholar, 17Zhang R. Zhao J. Potter J.D. J. Biol. Chem. 1995; 270: 30773-30780Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar) and increases the rate of cardiac muscle relaxation (18Robertson S.P. Johnson J.D. Holroyde M.J. Kranias E.G. Potter J.D. Solaro R.J. J. Biol. Chem. 1982; 257: 260-263Abstract Full Text PDF PubMed Google Scholar, 19Zhang R. Zhao J. Mandveno A. Potter J.D. Circ. Res. 1995; 76: 1028-1035Crossref PubMed Scopus (270) Google Scholar, 20Kentish J.C. McCloskey D.T. Layland J. Palmer S. Leiden J.M. Martin A.F. Solaro R.J. Circ. Res. 2001; 88: 1059-1065Crossref PubMed Scopus (263) Google Scholar, 21Wolska B.M. Arteaga G.M. Pena J.R. Nowak G. Phillips R.M. Sahai S. de Tombe P.P. Martin A.F. Kranias E.G. Solaro R.J. Circ. Res. 2002; 90: 882-888Crossref PubMed Scopus (50) Google Scholar). PKA-dependent cTnI phosphorylation is decreased in heart failure (22McConnell B.K. Moravec C.S. Bond M. Am. J. Physiol. 1998; 274: H385-H396PubMed Google Scholar, 23Zakhary D.R. Moravec C.S. Stewart R.W. Bond M. Circulation. 1999; 99: 505-510Crossref PubMed Scopus (117) Google Scholar). A restricted N-terminal truncation of cTnI occurs at low levels in normal heart and increases in adaptation to hemodynamic changes in the tail suspension rat model of simulated microgravity (24Yu Z.B. Zhang L.F. Jin J.-P. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). that the of TnI but the cTnI-specific N-terminal the PKA phosphorylation sites and Transgenic mouse hearts overexpressing the N-terminal truncated cTnI (cTnI-ND) demonstrated increased myocardial relaxation and ventricular for a of the the effect of PKA phosphorylation J.C. Bond M. Jin J.-P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). These that the β-adrenergic signaling pathway cTnI function by phosphorylation and to myocardial contraction. In the we that impaired β-adrenergic signaling resulting from myocardial Gsα deficiency leads to impaired cardiac function accompanied by an up-regulation of Overexpression of cTnI-ND in Gsα-DF hearts increased relaxation velocity and left ventricular end diastolic volume to produce higher left ventricle maximum pressure and stroke volume. Supporting the hypothesis that the up-regulation of cTnI-ND is a compensatory rather than a destructive myocardial response to impaired β-adrenergic signaling, cTnI-ND overexpression reversed the aberrant expression of β-myosin heavy chain in Gsα-DF hearts. These data indicate that up-regulation of cTnI-ND may partially compensate for the cardiac inefficiency in impaired β-adrenergic signaling, a for the treatment of heart of Gsα-DF in Cardiac with Gsα M. J. T. J. L. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar) with the muscle creatine kinase mice to of the Gsα The effect on Gsα expression or M. Zhao A. J. L. L. S. W. J. Clin. 2005; PubMed Scopus Google Scholar), and and used Gsα to and was by the M. Zhao A. J. L. L. S. W. J. Clin. 2005; PubMed Scopus Google Scholar). The or of the was by M. Zhao A. J. L. L. S. W. J. Clin. 2005; PubMed Scopus Google Scholar). on a and of used for in the The by the and and in with the in the and of by the of the Overexpression of cTnI-ND in Gsα-DF Cardiac have developed transgenic mouse overexpressing cTnI-ND in the cardiac muscle the control of J.C. Bond M. Jin J.-P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). transgenic mice generated by cTnI-ND transgenic mice with mice for cardiac functional The was by on from tail and hearts used for functional by for the of Gsα M. Zhao A. J. L. L. S. W. J. Clin. 2005; PubMed Scopus Google Scholar) and the overexpression of cTnI-ND J.C. Bond M. Jin J.-P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). and protein expression in the cardiac muscle was on protein by and a M. Zhao A. J. L. L. S. W. J. Clin. 2005; PubMed Scopus Google Scholar). Cardiac TnI and cTnI-ND by a J.-P. Z.B. Bond M. A. 2001; PubMed Scopus Google Scholar) and a the N-terminal of cTnI. phosphorylated protein in the was with a in for and to in for the for in a with to by in for the for in and on a for and for and of myosin heavy chain by and Z.B. F. Jin J.-P. Am. J. Physiol. PubMed Scopus Google Scholar). protein was from cardiac muscle by in heavy chain with a of in and The was of and The was and at in an for protein by with Heart and function of transgenic and mice was in heart J.C. Bond M. Jin J.-P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. Moravec Jin J.-P. Am. J. Physiol. Scopus Google Scholar, Jin J.-P. J. Physiol. Scopus Google Scholar). of of the mice with and the heart was A with a to the was used the A with a end was of the a to the a was used to the for the left A was used to the to the heart was to by the left In the hearts with with at to the of and The and at The of J. Mol. Cell Cardiol. 1998; Full Text PDF PubMed Scopus Google Scholar) and S. G. P. Physiol. 2002; PubMed Scopus Google Scholar) by substrates for mouse heart M.J. Clin. Pharmacol. Physiol. 2003; PubMed Scopus Google Scholar), the hearts to in for A was used to the left ventricle from the to a for the of a pressure-volume for pressure and volume at pressure was an pressure was in the to in The of the the pressure and the of the left ventricular on by we the at in for mouse which similar to that in S. Am. J. Physiol. 2005; PubMed Scopus Google Scholar). Heart rate was at or by an with two on the Cardiac by the and in by a of was to an to produce a from the to via a data system function of the hearts was for the the maximum rate of left ventricular pressure and left ventricular volume volume heart was from the of and to heart Cardiac at of the mouse heart and the of the pressure was and the was at J.C. Bond M. Jin J.-P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. Moravec Jin J.-P. Am. J. Physiol. Scopus Google Scholar, Jin J.-P. J. Physiol. Scopus Google Scholar). To the effect of Gsα-DF on cardiac function pressure ventricular was the from to of and was on at cardiac functional in a data The significance of the was by in the or Gsα in Cardiac in Heart with β-Adrenergic of ventricular muscle demonstrated that the level of Gsα protein was in the mouse hearts with that in The level of Gsα by in the heart may from muscle the and Cardiac TnI and myosin-binding protein C are two substrates of PKA of the Gsα signaling decreased phosphorylation level of the two proteins in in Gsα-DF the phosphorylation of cardiac troponin Although of hearts the phosphorylation of cTnI and myosin-binding protein the removal of sympathetic nervous treatment increased their phosphorylation levels in hearts but effect on that in Gsα-DF hearts the PKA phosphorylation that myocardial β-adrenergic signaling was impaired in of the Gsα-DF hearts was in heart The heart rate was in the from to by in the Gsα-DF hearts was in the left ventricular end diastolic volume. Cardiac function at and decreased and relaxation left ventricle maximum to pressure pressure stroke and decreased cardiac function of hearts in heart at and Heart by The hearts with in left ventricle end diastolic volume. The functional of hearts decreased myocardial left ventricular maximum left ventricular left ventricular end diastolic to to the the the the volume the the the the control in a The failing of Gsα-DF hearts was demonstrated by the of pressure-volume the from to the mouse hearts to and produce In not Gsα-DF hearts to of and Gsα-DF hearts that to that Gsα deficiency in in cardiac function at the increased are in with a decreased myocardial the increase in are in pressure volume for the of end pressure volume demonstrated the myocardial of Gsα-DF hearts of stroke from also decreased stroke in Gsα-DF hearts the increase in heart function at increased In with the function at cardiac function in response to pressure was by the to Although hearts to to produce of Gsα-DF hearts to with decreased left ventricular maximum left ventricular left ventricular end diastolic the the the volume the the the the control in a treatment of the heart impaired β-adrenergic signaling in the Gsα-DF hearts The heart rate of Gsα-DF hearts was to the of similar to that of β-adrenergic signaling in the produced and in hearts with increased velocity relaxation velocity left ventricular stroke and and left ventricular In or on functional in the Gsα-DF hearts Gsα-DF an of in the myofilament proteins of Gsα-DF hearts was an increase of a cTnI the C of TnI and an TnI N-terminal that cTnI the N-terminal an C that the cTnI was produced by restricted N-terminal similar to the cTnI produced in rat hearts hemodynamic adaptation to simulated microgravity (24Yu Z.B. Zhang L.F. Jin J.-P. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). of the that impaired β-adrenergic signaling increased the level of cTnI from to of cTnI restricted the cTnI-specific N-terminal the PKA phosphorylation sites and the functional (24Yu Z.B. Zhang L.F. Jin J.-P. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). Overexpression of cTnI-ND the of Gsα-DF have transgenic mice overexpressing cTnI-ND in the heart to on cardiac muscle relaxation and ventricular J.C. Bond M. Jin J.-P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). To investigate the functional significance of the increased cTnI-ND in Gsα-DF failing we generated double transgenic mice that overexpress cTnI-ND in the Gsα-DF hearts of the and their on the Gsα protein and overexpression of cTnI-ND in the cardiac muscle of the double transgenic mice heart that overexpression of cTnI-ND in Gsα-DF mouse hearts not ventricular velocity and left ventricle pressure but increased ventricular relaxation velocity maximum left ventricle maximum left ventricular end diastolic and stroke with the role of cTnI-ND in of the mechanism J.C. Bond M. Jin J.-P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar) The overexpression of cTnI-ND produced a of myocardial a of The in the decreased maximum left ventricle pressure and stroke heart failure in the Gsα-DF hearts and the of left ventricular end diastolic volume by overexpression of These that cTnI-ND overexpression partially the heart failure in Gsα-DF mice and the hypothesis that the increase in cTnI-ND expression in Gsα-DF hearts is a compensatory adaptation the heart failure from impaired β-adrenergic function of mouse hearts of hearts was with that of Gsα-DF hearts for the effect of cTnI-ND overexpression. of mice in heart The hearts with increased relaxation left ventricular end diastolic left ventricular maximum and stroke volume. The demonstrated that overexpression of cTnI-ND in Gsα-DF hearts partially the failing of β-adrenergic left ventricular maximum left ventricular left ventricular end diastolic maximum Gsα-DF by for Gsα-DF and for heart Gsα-DF by Gsα-DF by Gsα-DF by volume Gsα-DF by Gsα-DF by Gsα-DF by for Gsα-DF and for Gsα-DF by Gsα-DF by in a The hearts also or to the treatment of the function in with that of Gsα-DF hearts The that cTnI-ND for cardiac function of β-adrenergic signaling. Overexpression of cTnI-ND the of the in Gsα-DF of that ventricular muscle from mice and of of and the A and in Gsα-DF and mouse hearts. The of cardiac in was by and for and J.-P. 1990; PubMed Scopus Google Scholar) Although was in adult mouse in adult Gsα-DF hearts by of A and that the expression of was not a of Gsα deficiency but a response to the of heart hypothesis is with the that expression of in the adult ventricular muscle is to a compensatory response for A.M. Circulation. PubMed Scopus Google Scholar) and L. and Scholar) The expression of in adult hearts was by the overexpression of cTnI-ND These are in with the cardiac function, for the role of cTnI-ND in for myocardial impaired β-adrenergic signaling. Gsα in Heart have that overexpression of signaling in the β1-adrenergic pathway heart failure to the detrimental of myocardial hypertrophy, and degeneration (10Bristow M.R. Circulation. 2000; 101: 558-569Crossref PubMed Scopus (936) Google Scholar, 11Engelhardt S. Heart Fail. Clin. 2005; 1: 183-191Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 12Lohse M.J. Engelhardt S. Eschenhagen T. Circ. Res. 2003; 93: 896-906Crossref PubMed Scopus (602) Google Scholar). mice to and normal but the and to J.R. M.E. G.S. D. B.K. Proc. Natl. Acad. Sci. U. S. A. 93: PubMed Scopus Google Scholar). that the expression of Gsα protein in mouse cardiac muscle, which β1-adrenergic signaling, produced function and heart failure The Gsα-DF failing hearts decreased heart functional at and to pressure Gsα-DF hearts also β-adrenergic decreased in phosphorylation of cTnI and myosin-binding protein C Although of the hearts the phosphorylation levels of cTnI and myosin-binding protein β-adrenergic in the the phosphorylation of cTnI and myosin-binding protein C in hearts but effect on the Gsα-DF hearts a of PKA The of PKA in Gsα-DF is to the phosphorylation of proteins that the Ca2+ handling system, the ryanodine and phospholamban in sarcoplasmic to of cardiac A. T. Y. T. K. R. T. T. T. Circ. J. 2003; PubMed Scopus Google Scholar), which in decreased and diastolic function in the Gsα-DF hearts. that β-adrenergic stimulation protein kinase in a to cardiac muscle relaxation phosphorylation of phospholamban S. A. K. K. N. M. Res. PubMed Scopus Google Scholar). the role of signaling pathway in Gsα-DF hearts to Although the Gsα-DF mouse heart is not a heart failure a system to investigate the in myocardial adaptation to β-adrenergic cTnI-ND in Gsα-DF cTnI-ND is produced at low levels in normal cardiac muscle and in adaptation (24Yu Z.B. Zhang L.F. Jin J.-P. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). in the is that the myocardial Gsα heart failure was accompanied by an increased level of N-terminal truncated cTnI. The PKA phosphorylation sites in cTnI are two adjacent N-terminal serine residues, Ser23/Ser24 (rat/mouse residue numbers), in the N-terminal extension. A demonstrated that PKA phosphorylation increases the of cardiac TnI to I F. R. F. R. N. S. S. J. 1995; PubMed Scopus Google Scholar). with the PKA to Gsα the level of cTnI phosphorylation was in Gsα-DF hearts. is that PKA phosphorylation in the Gsα-DF cardiac muscle of cTnI. The N-terminal truncation of which was in myocardial adaptation to hemodynamic changes in simulated is a restricted that the of TnI (24Yu Z.B. Zhang L.F. Jin J.-P. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). In to the truncation of which a of TnI and myocardial A.M. D. 2000; PubMed Scopus Google Scholar), overexpression of cTnI-ND in transgenic mouse hearts in a cardiac with increased myocardial relaxation and ventricular for a of the mechanism J.C. Bond M. Jin J.-P. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of cTnI to a of β-Adrenergic demonstrated that PKA phosphorylation of the two N-terminal in cTnI reduces myofilament Ca2+ sensitivity (7Kranias E.G. Solaro R.J. Nature. 1982; 298: 182-184Crossref PubMed Scopus (177) Google Scholar, 17Zhang R. Zhao J. Potter J.D. J. Biol. Chem. 1995; 270: 30773-30780Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar) and increases the rate of myocardial relaxation (18Robertson S.P. Johnson J.D. Holroyde M.J. Kranias E.G. Potter J.D. Solaro R.J. J. Biol. Chem. 1982; 257: 260-263Abstract Full Text PDF PubMed Google Scholar, 19Zhang R. Zhao J. Mandveno A. Potter J.D. Circ. Res. 1995; 76: 1028-1035Crossref PubMed Scopus (270) Google Scholar, 20Kentish J.C. McCloskey D.T. Layland J. Palmer S. Leiden J.M. Martin A.F. Solaro R.J. Circ. Res. 2001; 88: 1059-1065Crossref PubMed Scopus (263) Google Scholar). The phosphorylation of cTnI is a of the myocardial to β-adrenergic stimulation B.M. Arteaga G.M. Pena J.R. Nowak G. Phillips R.M. Sahai S. de Tombe P.P. Martin A.F. Kranias E.G. Solaro R.J. Circ. Res. 2002; 90: 882-888Crossref PubMed Scopus (50) Google Scholar). PKA phosphorylation of cTnI to ventricular relaxation in the Gsα-DF hearts. To the hypothesis that cTnI-ND is a compensatory rather than a destructive response to impaired β-adrenergic signaling, we cTnI-ND in the Gsα-DF hearts with a and demonstrated that cTnI-ND overexpression cardiac function, with increased relaxation left ventricular maximum and stroke volume. The indicate that cTnI-ND partially compensate for the in myocardial relaxation velocity by Gsα the effect of phosphorylation of cTnI. The effect of removal of the N-terminal extension of cTnI on cardiac muscle relaxation that of PKA phosphorylation of In to the of PKA phosphorylation on cardiac muscle function, the restricted N-terminal truncation of cTnI a mechanism of β-adrenergic signaling to cardiac function of the that the of in the treatment of heart N-terminal of cTnI a for the of Heart normal adult ventricular muscle the low level expression of is in failing adult ventricular The of of was from in hearts to in end failing to a of protein to S. Minobe W. M.R. Circ. 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Full Text Full Text PDF PubMed Scopus Google Scholar), a compensatory role in the of chronic heart The level of in hearts was than that in Gsα-DF hearts at of effect of cTnI-ND overexpression the functional of overexpressing cTnI-ND in Gsα-DF failing which the for the compensatory response. The level of in the ventricular muscle to the function, the maximum left ventricle of hearts. the of cTnI function is a of the β-adrenergic mechanism in cardiac muscle contractility, the transgenic expression of cTnI-ND not fully the function of Gsα-DF hearts. is also that the stroke volume of the hearts was accompanied by a increase in ventricular end diastolic left ventricular the effect on dilated cardiomyopathy to the function of hearts demonstrated the of increased cTnI-ND in Gsα-DF hearts an response to heart In the mouse demonstrated a of the regulation in cardiac muscle that for the decreased cardiac function resulting from impaired β-adrenergic signaling. The restricted N-terminal truncation of cTnI a mechanism in myocardial for the mouse cardiac and for the of transgenic