Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure

To determine whether selective impairment of cardiac sarcoplasmic reticulum (SR) Ca2+ transport may drive the progressive functional deterioration leading to heart failure, transgenic mice, overexpressing a phospholamban Val49 → Gly mutant (2-fold), which is a superinhibitor of SR Ca2+-ATPase affinity for Ca2+, were generated, and their cardiac phenotype was examined longitudinally. At 3 months of age, the increased EC50 level of SR Ca2+ uptake for Ca2+ (0.67 ± 0.09 μm) resulted in significantly higher depression of cardiomyocyte rates of shortening (57%), relengthening (31%), and prolongation of the Ca2+ signal decay time (165%) than overexpression (2-fold) of wild type phospholamban (68%, 64%, and 125%, respectively), compared with controls (100%). Echocardiography also revealed significantly depressed function and impaired β-adrenergic responses in mutant hearts. The depressed contractile parameters were associated with left ventricular remodeling, recapitulation of fetal gene expression, and hypertrophy, which progressed to dilated cardiomyopathy with interstitial tissue fibrosis and death by 6 months in males. Females also had ventricular hypertrophy at 3 months but exhibited normal systolic function up to 12 months of age. These results suggest a causal relationship between defective SR Ca2+ cycling and cardiac remodeling leading to heart failure, with a gender-dependent influence on the time course of these alterations. To determine whether selective impairment of cardiac sarcoplasmic reticulum (SR) Ca2+ transport may drive the progressive functional deterioration leading to heart failure, transgenic mice, overexpressing a phospholamban Val49 → Gly mutant (2-fold), which is a superinhibitor of SR Ca2+-ATPase affinity for Ca2+, were generated, and their cardiac phenotype was examined longitudinally. At 3 months of age, the increased EC50 level of SR Ca2+ uptake for Ca2+ (0.67 ± 0.09 μm) resulted in significantly higher depression of cardiomyocyte rates of shortening (57%), relengthening (31%), and prolongation of the Ca2+ signal decay time (165%) than overexpression (2-fold) of wild type phospholamban (68%, 64%, and 125%, respectively), compared with controls (100%). Echocardiography also revealed significantly depressed function and impaired β-adrenergic responses in mutant hearts. The depressed contractile parameters were associated with left ventricular remodeling, recapitulation of fetal gene expression, and hypertrophy, which progressed to dilated cardiomyopathy with interstitial tissue fibrosis and death by 6 months in males. Females also had ventricular hypertrophy at 3 months but exhibited normal systolic function up to 12 months of age. These results suggest a causal relationship between defective SR Ca2+ cycling and cardiac remodeling leading to heart failure, with a gender-dependent influence on the time course of these alterations. sarcoplasmic reticulum phospholamban mutant phospholamban a mutant form of phospholamban in which Val49 is mutated to Gly cardiac sarcoplasmic reticulum, Ca2+-ATPase human embryonic kidney α- and β-myosin heavy chain atrial natriuretic peptide kilobase pair(s) L-type Ca2+ current left ventricular picofarads Cardiac hypertrophy and failure are highly complex disorders that arise as a result of a combination of mechanical, hemodynamic, hormonal, and pathological stimuli (1Levy D. Garrison R.J. Savage D.D. Kannel W.B. Castelli W.P. N. Engl. J. Med. 1990; 322: 1561-1566Crossref PubMed Scopus (4810) Google Scholar). In response to these effectors, the heart undergoes an adaptive response of compensatory hypertrophy (2Chien K.R. Cell. 1999; 98: 555-558Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar) followed by decompensated heart failure that is characterized by defects in Ca2+ handling during excitation-contraction coupling. Studies of end-stage-failing hearts have shown that the disturbed calcium homeostasis is associated with alterations in the expression levels or the activity of key Ca2+-handling proteins, leading to abnormal excitation contraction coupling and diastolic as well as systolic dysfunction (3Hasenfuss G. Cardiovasc. Res. 1998; 39: 60-76Crossref PubMed Scopus (338) Google Scholar, 4Houser S.R. Piacentino 3rd, V. Weisser J. J. Mol. Cell Cardiol. 2000; 32: 1595-1607Abstract Full Text PDF PubMed Scopus (278) Google Scholar). Specifically, alterations in SR1Ca2+-ATPase (SERCA2a) activity, the major Ca2+transport protein in SR, have been implicated as important determinants in the deteriorated function of the failing heart (5Meyer M. Schillinger W. Pieske B. Holubarsch C. Heilmann C. Posival H. Kuwajima G. Mikoshiba K. Just H. Hasenfuss G. Circulation. 1995; 92: 778-784Crossref PubMed Scopus (440) Google Scholar, 6Schmidt U. Hajjar R.J. Kim C.S. Lebeche D. Doye A.A. Gwathmey J.K. Am. J. Physiol. 1999; 277: H474-H480Crossref PubMed Google Scholar, 7Schwinger R.H. Munch G. Bolck B. Karczewski P. Krause E.G. Erdmann E. J. Mol. Cell Cardiol. 1999; 31: 479-491Abstract Full Text PDF PubMed Scopus (243) Google Scholar). The activity of SERCA2a is regulated by phospholamban (PLB), a 52-amino acid, muscle-specific SR phosphoprotein (8Koss K.L. Kranias E.G. Circ. Res. 1996; 79: 1059-1063Crossref PubMed Scopus (288) Google Scholar, 9Simmerman H.K. Jones L.R. Physiol. Rev. 1998; 78: 921-947Crossref PubMed Scopus (461) Google Scholar, 10Tada M. Yabuki M. Toyofuku T. Ann. N. Y. Acad. Sci. 1998; 853: 116-129Crossref PubMed Scopus (12) Google Scholar). Dephosphorylated the Ca2+ affinity of the form of SERCA2a leading to in Ca2+ uptake rates and ventricular W. G. Y. Kranias E.G. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, H.K. Jones L.R. J. Full Text PDF PubMed Google Scholar, M. M. M. M. Mol. Cell PubMed Scopus Google of in the of been the of resulted in in cardiac contractile overexpressing was associated with depressed cardiac function Kranias E.G. J. 1996; PubMed Scopus Google Scholar, W. J. G. T. Kranias E.G. Circ. Res. PubMed Scopus Google Scholar). an relationship between the of and was K.L. Kranias E.G. Res. Cardiol. 92: PubMed Google that that the levels of these the between may result in is whether a in SR Ca2+ by between and may result in depressed and drive the progressive deterioration of function leading to heart the between and SERCA2a were the which the in T. K. M. J. Full Text PDF PubMed Google Scholar, L.R. J. Full Text PDF PubMed Google Scholar). the were shown to the of on SERCA2a with increased the on SERCA2a in Y. K. M. J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. M. K. M. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Jones L.R. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of these to in that overexpression of or mutant resulted in depressed cardiac Ca2+ and parameters associated with hypertrophy E. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). for the functional of the in on SERCA2a was by a in which a Val49 → mutant was in The mutant to in cardiac ventricular in the of M. G. K. Y. Y. J. Kranias E.G. K.R. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the of the in with SERCA2a and that with may a for the of dilated To the functional of the Val49 in a Val49 → Gly which as a of the Ca2+ affinity of overexpression of the mutant resulted in of cardiac and cardiac remodeling, which progressed to dilated cardiomyopathy and of SERCA2a by may as a for the and of heart is the to that a in which is associated with of SERCA2a and contractile may to dilated heart failure, and which are by in or human with heart failure that the in diastolic calcium and impaired were to of SR Ca2+ transport (3Hasenfuss G. Cardiovasc. Res. 1998; 39: 60-76Crossref PubMed Scopus (338) Google Scholar, N. Engl. J. Med. PubMed Scopus Google Scholar). the depressed SR function was to to and may as a for the of cardiac deterioration K.R. J. 2000; PubMed Scopus Google Scholar). is whether of SR Ca2+ transport is to heart failure or is a to cardiomyocyte dysfunction in the of heart To the of depressed SR Ca2+ transport activity in the and of heart failure, a transgenic the in which as a superinhibitor of SERCA2a Ca2+ affinity in and the cardiac phenotype the of the of mutant was associated with depression in SR Ca2+ uptake The SR function resulted in impaired cardiac contractile parameters in and at 3 months of age. In the parameters a prolongation in the of the Ca2+ signal decay in the of the Ca2+ The of may increased Ca2+ the L-type Ca2+ was increased in transgenic an important compensatory response in an to systolic Ca2+ levels in these The mutant also exhibited significantly increased Ca2+ the L-type Ca2+ that the SR Ca2+ was H. Y. W. Kranias E.G. Am. J. Physiol. Google Scholar, M. Acad. Sci. U. 1995; 92: PubMed Scopus Google Scholar). alterations were exhibited in a which the levels of mutant that the was to expression and the of mutant in are with a a mutant M. G. K. Y. Y. J. Kranias E.G. K.R. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google that the Val49 in which is highly is important for the and in have on SR function and cardiac the in may influence the of and with the normal of to was by in that the of the mutant may to between and SERCA2a with the of to the mutant to with the mutant J. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In the in and mutant by E. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google is of that overexpression of the mutant cardiac hypertrophy in an to cardiac function Circulation. 2000; PubMed Scopus Google Scholar, W. Am. J. Med. Full Text PDF PubMed Scopus Google which was depressed in mutant hearts. the that depressed SR Ca2+ cycling to of gene expression in the hearts are was associated with or of a fetal gene β-myosin heavy and in these hearts Circ. Res. PubMed Scopus Google Scholar). The in the protein expression levels of the heavy chain 1998; Full Text Full Text PDF PubMed Google Scholar) may also to the of contraction and rates in the mutant hearts. the remodeling, which an compensatory progressed to cardiac failure and death in the on the J. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and and E. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) also depressed SR and cardiac function in which were associated with hypertrophy by 3 months of age. the phenotype of the and mutant to heart failure, as with the The between these transgenic may to the expression levels of the in the of the the time course of between the compensatory response and heart In may in by SR which to of these transgenic the and in E. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. K. Y. Y. J. Kranias E.G. K.R. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, T. T. C.S. J. 2000; PubMed Scopus Google Scholar) suggest that disturbed SR Ca2+ may in to a response leading to heart have that is higher in than in which cardiac and a gender-dependent influence on the and of heart failure M. B. K. W. J. Circulation. 1999; PubMed Google Scholar). In the also an in compared with in with SR Ca2+-handling The in was to in their levels of compared with males. in cardiac function and in the to heart and were examined during compensatory hypertrophy and the of of heart failure, was increased by 3 months of age, and cardiac function was significantly depressed in mutant The remodeling the to heart failure, characterized by and a in the of to by 6 months of age. the to failure was in T. T. C.S. J. 2000; PubMed Scopus Google a of hypertrophy between and were in the response to pathological hypertrophy and depressed to in the overexpression and in a of hypertrophy J. M. J. Am. Cardiol. 1999; PubMed Scopus Google Scholar). The of these is but may a adaptive in M. K. E. Circulation. PubMed Scopus Google the and activity in H. Circ. Res. PubMed Scopus Google a higher of the which is by in G. J. Circ. Res. PubMed Scopus Google and the in cardiac and P. J. Circulation. PubMed Scopus Google Scholar). the may to in gene expression in pathological hypertrophy C. K. M. R.H. H. PubMed Scopus Google Scholar). in with and cardiac hypertrophy, to an of contraction on Am. J. Cardiol. Full Text PDF PubMed Scopus Google which is to that in mutant in to a in SR function as an of a phenotype that human dilated cardiomyopathy and ventricular The of SERCA2a by the mutant associated with depressed calcium resulted in a remodeling which between of the leading to heart significantly the of the responses to remodeling, the to heart failure in the mutant on the and these gene expression and may or by which depressed SR function the of hypertrophy and the to dilated cardiomyopathy in Cardiac hypertrophy and failure are highly complex disorders that arise as a result of a combination of mechanical, hemodynamic, hormonal, and pathological stimuli (1Levy D. Garrison R.J. Savage D.D. Kannel W.B. Castelli W.P. N. Engl. J. Med. 1990; 322: 1561-1566Crossref PubMed Scopus (4810) Google Scholar). In response to these effectors, the heart undergoes an adaptive response of compensatory hypertrophy (2Chien K.R. Cell. 1999; 98: 555-558Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar) followed by decompensated heart failure that is characterized by defects in Ca2+ handling during excitation-contraction coupling. Studies of end-stage-failing hearts have shown that the disturbed calcium homeostasis is associated with alterations in the expression levels or the activity of key Ca2+-handling proteins, leading to abnormal excitation contraction coupling and diastolic as well as systolic dysfunction (3Hasenfuss G. Cardiovasc. Res. 1998; 39: 60-76Crossref PubMed Scopus (338) Google Scholar, 4Houser S.R. Piacentino 3rd, V. Weisser J. J. Mol. Cell Cardiol. 2000; 32: 1595-1607Abstract Full Text PDF PubMed Scopus (278) Google Scholar). Specifically, alterations in SR1Ca2+-ATPase (SERCA2a) activity, the major Ca2+transport protein in SR, have been implicated as important determinants in the deteriorated function of the failing heart (5Meyer M. Schillinger W. Pieske B. Holubarsch C. Heilmann C. Posival H. Kuwajima G. Mikoshiba K. Just H. Hasenfuss G. Circulation. 1995; 92: 778-784Crossref PubMed Scopus (440) Google Scholar, 6Schmidt U. Hajjar R.J. Kim C.S. Lebeche D. Doye A.A. Gwathmey J.K. Am. J. Physiol. 1999; 277: H474-H480Crossref PubMed Google Scholar, 7Schwinger R.H. Munch G. Bolck B. Karczewski P. Krause E.G. Erdmann E. J. Mol. Cell Cardiol. 1999; 31: 479-491Abstract Full Text PDF PubMed Scopus (243) Google Scholar). The activity of SERCA2a is regulated by phospholamban (PLB), a 52-amino acid, muscle-specific SR phosphoprotein (8Koss K.L. Kranias E.G. Circ. Res. 1996; 79: 1059-1063Crossref PubMed Scopus (288) Google Scholar, 9Simmerman H.K. Jones L.R. Physiol. Rev. 1998; 78: 921-947Crossref PubMed Scopus (461) Google Scholar, 10Tada M. Yabuki M. Toyofuku T. Ann. N. Y. Acad. Sci. 1998; 853: 116-129Crossref PubMed Scopus (12) Google Scholar). Dephosphorylated the Ca2+ affinity of the form of SERCA2a leading to in Ca2+ uptake rates and ventricular W. G. Y. Kranias E.G. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, H.K. Jones L.R. J. Full Text PDF PubMed Google Scholar, M. M. M. M. Mol. Cell PubMed Scopus Google Scholar). The of in the of been the of resulted in in cardiac contractile overexpressing was associated with depressed cardiac function Kranias E.G. J. 1996; PubMed Scopus Google Scholar, W. J. G. T. Kranias E.G. Circ. Res. PubMed Scopus Google Scholar). an relationship between the of and was K.L. Kranias E.G. Res. Cardiol. 92: PubMed Google that that the levels of these the between may result in is whether a in SR Ca2+ by between and may result in depressed and drive the progressive deterioration of function leading to heart the between and SERCA2a were the which the in T. K. M. J. Full Text PDF PubMed Google Scholar, L.R. J. Full Text PDF PubMed Google Scholar). the were shown to the of on SERCA2a with increased the on SERCA2a in Y. K. M. J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. M. K. M. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Jones L.R. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of these to in that overexpression of or mutant resulted in depressed cardiac Ca2+ and parameters associated with hypertrophy E. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). for the functional of the in on SERCA2a was by a in which a Val49 → mutant was in The mutant to in cardiac ventricular in the of M. G. K. Y. Y. J. Kranias E.G. K.R. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the of the in with SERCA2a and that with may a for the of dilated To the functional of the Val49 in a Val49 → Gly which as a of the Ca2+ affinity of overexpression of the mutant resulted in of cardiac and cardiac remodeling, which progressed to dilated cardiomyopathy and of SERCA2a by may as a for the and of heart is the to that a in which is associated with of SERCA2a and contractile may to dilated heart failure, and which are by in or human with heart failure that the in diastolic calcium and impaired were to of SR Ca2+ transport (3Hasenfuss G. Cardiovasc. Res. 1998; 39: 60-76Crossref PubMed Scopus (338) Google Scholar, N. Engl. J. Med. PubMed Scopus Google Scholar). the depressed SR function was to to and may as a for the of cardiac deterioration K.R. J. 2000; PubMed Scopus Google Scholar). is whether of SR Ca2+ transport is to heart failure or is a to cardiomyocyte dysfunction in the of heart To the of depressed SR Ca2+ transport activity in the and of heart failure, a transgenic the in which as a superinhibitor of SERCA2a Ca2+ affinity in and the cardiac phenotype the of the of mutant was associated with depression in SR Ca2+ uptake The SR function resulted in impaired cardiac contractile parameters in and at 3 months of age. In the parameters a prolongation in the of the Ca2+ signal decay in the of the Ca2+ The of may increased Ca2+ the L-type Ca2+ was increased in transgenic an important compensatory response in an to systolic Ca2+ levels in these The mutant also exhibited significantly increased Ca2+ the L-type Ca2+ that the SR Ca2+ was H. Y. W. Kranias E.G. Am. J. Physiol. Google Scholar, M. Acad. Sci. U. 1995; 92: PubMed Scopus Google Scholar). alterations were exhibited in a which the levels of mutant that the was to expression and the of mutant in are with a a mutant M. G. K. Y. Y. J. Kranias E.G. K.R. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google that the Val49 in which is highly is important for the and in have on SR function and cardiac the in may influence the of and with the normal of to was by in that the of the mutant may to between and SERCA2a with the of to the mutant to with the mutant J. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In the in and mutant by E. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google is of that overexpression of the mutant cardiac hypertrophy in an to cardiac function Circulation. 2000; PubMed Scopus Google Scholar, W. Am. J. Med. Full Text PDF PubMed Scopus Google which was depressed in mutant hearts. the that depressed SR Ca2+ cycling to of gene expression in the hearts are was associated with or of a fetal gene β-myosin heavy and in these hearts Circ. Res. PubMed Scopus Google Scholar). The in the protein expression levels of the heavy chain 1998; Full Text Full Text PDF PubMed Google Scholar) may also to the of contraction and rates in the mutant hearts. the remodeling, which an compensatory progressed to cardiac failure and death in the on the J. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and and E. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) also depressed SR and cardiac function in which were associated with hypertrophy by 3 months of age. the phenotype of the and mutant to heart failure, as with the The between these transgenic may to the expression levels of the in the of the the time course of between the compensatory response and heart In may in by SR which to of these transgenic the and in E. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. K. Y. Y. J. Kranias E.G. K.R. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, T. T. C.S. J. 2000; PubMed Scopus Google Scholar) suggest that disturbed SR Ca2+ may in to a response leading to heart have that is higher in than in which cardiac and a gender-dependent influence on the and of heart failure M. B. K. W. J. Circulation. 1999; PubMed Google Scholar). In the also an in compared with in with SR Ca2+-handling The in was to in their levels of compared with males. in cardiac function and in the to heart and were examined during compensatory hypertrophy and the of of heart failure, was increased by 3 months of age, and cardiac function was significantly depressed in mutant The remodeling the to heart failure, characterized by and a in the of to by 6 months of age. the to failure was in T. T. C.S. J. 2000; PubMed Scopus Google a of hypertrophy between and were in the response to pathological hypertrophy and depressed to in the overexpression and in a of hypertrophy J. M. J. Am. Cardiol. 1999; PubMed Scopus Google Scholar). The of these is but may a adaptive in M. K. E. Circulation. PubMed Scopus Google the and activity in H. Circ. Res. PubMed Scopus Google a higher of the which is by in G. J. Circ. Res. PubMed Scopus Google and the in cardiac and P. J. Circulation. PubMed Scopus Google Scholar). the may to in gene expression in pathological hypertrophy C. K. M. R.H. H. PubMed Scopus Google Scholar). in with and cardiac hypertrophy, to an of contraction on Am. J. Cardiol. Full Text PDF PubMed Scopus Google which is to that in mutant in to a in SR function as an of a phenotype that human dilated cardiomyopathy and ventricular The of SERCA2a by the mutant associated with depressed calcium resulted in a remodeling which between of the leading to heart significantly the of the responses to remodeling, the to heart failure in the mutant on the and these gene expression and may or by which depressed SR function the of hypertrophy and the to dilated cardiomyopathy in is the to that a in which is associated with of SERCA2a and contractile may to dilated heart failure, and which are by in or human with heart failure that the in diastolic calcium and impaired were to of SR Ca2+ transport (3Hasenfuss G. Cardiovasc. Res. 1998; 39: 60-76Crossref PubMed Scopus (338) Google Scholar, N. Engl. J. Med. PubMed Scopus Google Scholar). the depressed SR function was to to and may as a for the of cardiac deterioration K.R. J. 2000; PubMed Scopus Google Scholar). is whether of SR Ca2+ transport is to heart failure or is a to cardiomyocyte dysfunction in the of heart To the of depressed SR Ca2+ transport activity in the and of heart failure, a transgenic the in which as a superinhibitor of SERCA2a Ca2+ affinity in and the cardiac phenotype the of the of mutant was associated with depression in SR Ca2+ uptake The SR function resulted in impaired cardiac contractile parameters in and at 3 months of age. In the parameters a prolongation in the of the Ca2+ signal decay in the of the Ca2+ The of may increased Ca2+ the L-type Ca2+ was increased in transgenic an important compensatory response in an to systolic Ca2+ levels in these The mutant also exhibited significantly increased Ca2+ the L-type Ca2+ that the SR Ca2+ was H. Y. W. Kranias E.G. Am. J. Physiol. Google Scholar, M. Acad. Sci. U. 1995; 92: PubMed Scopus Google Scholar). alterations were exhibited in a which the levels of mutant that the was to expression and The the of mutant in are with a a mutant M. G. K. Y. Y. J. Kranias E.G. K.R. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google that the Val49 in which is highly is important for the and in have on SR function and cardiac the in may influence the of and with the normal of to was by in that the of the mutant may to between and SERCA2a with the of to the mutant to with the mutant J. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In the in and mutant by E. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is of that overexpression of the mutant cardiac hypertrophy in an to cardiac function Circulation. 2000; PubMed Scopus Google Scholar, W. Am. J. Med. Full Text PDF PubMed Scopus Google which was depressed in mutant hearts. the that depressed SR Ca2+ cycling to of gene expression in the hearts are was associated with or of a fetal gene β-myosin heavy and in these hearts Circ. Res. PubMed Scopus Google Scholar). The in the protein expression levels of the heavy chain 1998; Full Text Full Text PDF PubMed Google Scholar) may also to the of contraction and rates in the mutant hearts. the remodeling, which an compensatory progressed to cardiac failure and death in the on the J. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and and E. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) also depressed SR and cardiac function in which were associated with hypertrophy by 3 months of age. the phenotype of the and mutant to heart failure, as with the The between these transgenic may to the expression levels of the in the of the the time course of between the compensatory response and heart In may in by SR which to of these transgenic the and in E. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. G. K. Y. Y. J. Kranias E.G. K.R. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Y. Kranias E.G. J. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, T. T. C.S. J. 2000; PubMed Scopus Google Scholar) suggest that disturbed SR Ca2+ may in to a response leading to heart have that is higher in than in which cardiac and a gender-dependent influence on the and of heart failure M. B. K. W. J. Circulation. 1999; PubMed Google Scholar). In the also an in compared with in with SR Ca2+-handling The in was to in their levels of compared with males. in cardiac function and in the to heart and were examined during compensatory hypertrophy and the of of heart failure, was increased by 3 months of age, and cardiac function was significantly depressed in mutant The remodeling the to heart failure, characterized by and a in the of to by 6 months of age. the to failure was in T. T. C.S. J. 2000; PubMed Scopus Google a of hypertrophy between and were in the response to pathological hypertrophy and depressed to in the overexpression and in a of hypertrophy J. M. J. Am. Cardiol. 1999; PubMed Scopus Google Scholar). The of these is but may a adaptive in M. K. E. Circulation. PubMed Scopus Google the and activity in H. Circ. Res. PubMed Scopus Google a higher of the which is by in G. J. Circ. Res. PubMed Scopus Google and the in cardiac and P. J. Circulation. PubMed Scopus Google Scholar). the may to in gene expression in pathological hypertrophy C. K. M. R.H. H. PubMed Scopus Google Scholar). in with and cardiac hypertrophy, to an of contraction on Am. J. Cardiol. Full Text PDF PubMed Scopus Google which is to that in mutant in In to a in SR function as an of a phenotype that human dilated cardiomyopathy and ventricular The of SERCA2a by the mutant associated with depressed calcium resulted in a remodeling which between of the leading to heart significantly the of the responses to remodeling, the to heart failure in the mutant on the and these gene expression and may or by which depressed SR function the of hypertrophy and the to dilated cardiomyopathy in

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