Defective β-Adrenergic Receptor Signaling Precedes the Development of Dilated Cardiomyopathy in Transgenic Mice with Calsequestrin Overexpression

Calsequestrin is a high capacity Ca2+-binding protein in the junctional sarcoplasmic reticulum that forms a quaternary complex with junctin, triadin, and the ryanodine receptor. Transgenic mice with cardiac-targeted calsequestrin overexpression show marked suppression of Ca2+-induced Ca2+ release, myocyte hypertrophy, and premature death by 16 weeks of age (Jones, L. R., Suzuki, Y. J., Wang, W., Kobayashi, Y. M., Ramesh, V., Franzini-Armstrong, C., Cleemann, L., and Morad, M. (1998)J. Clin. Invest. 101, 1385–1393). To investigate whether alterations in intracellular Ca2+ trigger changes in the β-adrenergic receptor pathway, we studied calsequestrin overexpressing transgenic mice at 7 and 14 weeks of age. As assessed by echocardiography, calsequestrin mice at 7 weeks showed mild left ventricular enlargement, mild decreased fractional shortening with increased wall thickness. By 14 weeks, the phenotype progressed to marked left ventricular enlargement and severely depressed systolic function. Cardiac catheterization in calsequestrin mice revealed markedly impaired β-adrenergic receptor responsiveness in both 7- and 14- week mice. Biochemical analysis in 7- and 14-week mice showed a significant decrease in total β-adrenergic receptor density, adenylyl cyclase activity, and the percent high affinity agonist binding, which was associated with increased β-adrenergic receptor kinase 1 levels. Taken together, these data indicate that alterations in β-adrenergic receptor signaling precede the development of overt heart failure in this mouse model of progressive cardiomyopathy. Calsequestrin is a high capacity Ca2+-binding protein in the junctional sarcoplasmic reticulum that forms a quaternary complex with junctin, triadin, and the ryanodine receptor. Transgenic mice with cardiac-targeted calsequestrin overexpression show marked suppression of Ca2+-induced Ca2+ release, myocyte hypertrophy, and premature death by 16 weeks of age (Jones, L. R., Suzuki, Y. J., Wang, W., Kobayashi, Y. M., Ramesh, V., Franzini-Armstrong, C., Cleemann, L., and Morad, M. (1998)J. Clin. Invest. 101, 1385–1393). To investigate whether alterations in intracellular Ca2+ trigger changes in the β-adrenergic receptor pathway, we studied calsequestrin overexpressing transgenic mice at 7 and 14 weeks of age. As assessed by echocardiography, calsequestrin mice at 7 weeks showed mild left ventricular enlargement, mild decreased fractional shortening with increased wall thickness. By 14 weeks, the phenotype progressed to marked left ventricular enlargement and severely depressed systolic function. Cardiac catheterization in calsequestrin mice revealed markedly impaired β-adrenergic receptor responsiveness in both 7- and 14- week mice. Biochemical analysis in 7- and 14-week mice showed a significant decrease in total β-adrenergic receptor density, adenylyl cyclase activity, and the percent high affinity agonist binding, which was associated with increased β-adrenergic receptor kinase 1 levels. Taken together, these data indicate that alterations in β-adrenergic receptor signaling precede the development of overt heart failure in this mouse model of progressive cardiomyopathy. Cardiac hypertrophy represents one of the most important adaptive responses to increase mechanical load on the heart. In an attempt to normalize excessive forces and work performed per contractile unit, myocardial hypertrophy unloads the heart by adding new sarcomeres in order to distribute tension across a greater cellular mass (1Grossman W. Jones D. McLaurin L.P. J. Clin. Invest. 1975; 56: 56-64Crossref PubMed Scopus (1869) Google Scholar). Although the induction of cardiac hypertrophy can be viewed as a corrective response to elevated stress, it is now clear that sustained hypertrophy initiates a myopathic process leading to decompensated heart failure (2Lorell B.H. Circulation. 1997; 96: 3824-3827PubMed Google Scholar). The molecular mechanisms that are responsible for this transition from a compensatory state to one of progressive chamber enlargement and myocardial failure are poorly understood. Derangement in a number of cellular processes have been implicated in this pathological transition including abnormalities in β-adrenergic receptor (βAR) 1The abbreviations used are: βAR, β-adrenergic receptor; βARK1, β-adrenergic receptor kinase 1; GRK, G protein-coupled receptor kinase; CSQ, calsequestrin; LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; % FS, % fractional shortening; SEPth, septal wall thickness; PWth, posterior wall thickness; LV dP/dtmax and LV dP/dtmin, maximal and minimal first derivative of LV pressure, respectively; mVcfc, heart rate corrected mean velocity of circumferential shortening 1The abbreviations used are: βAR, β-adrenergic receptor; βARK1, β-adrenergic receptor kinase 1; GRK, G protein-coupled receptor kinase; CSQ, calsequestrin; LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; % FS, % fractional shortening; SEPth, septal wall thickness; PWth, posterior wall thickness; LV dP/dtmax and LV dP/dtmin, maximal and minimal first derivative of LV pressure, respectively; mVcfc, heart rate corrected mean velocity of circumferential shortening signaling (3Eichhorn E.J. Bristow M.R. Circulation. 1996; 94: 2285-2296Crossref PubMed Scopus (441) Google Scholar), activation of mitogen-activated protein kinase pathways (4Force T. Bonventre J.V. Hypertension. 1998; 31 Suppl. S: 152-161Crossref Google Scholar), and diminished excitation-contraction coupling due to an altered spatial relationship between the L-type Ca2+ channel and the ryanodine receptor (5Gomez A.M. Valdivia H.H. Cheng H. Lederer M.R. Santana L.F. Cannell M.B. McCune S.A. Altschuld R.A. Lederer W.J. Science. 1997; 276: 800-806Crossref PubMed Scopus (642) Google Scholar). Chronic human heart failure is characterized by marked abnormalities in βAR signaling that result from a number of alterations including a 50% reduction in β1ARs without change in β2AR density (6Bristow M.R. Lancet. 1998; 352 Suppl. I: 8-14Abstract Full Text Full Text PDF Google Scholar), increased levels of the inhibitory G protein (6Bristow M.R. Lancet. 1998; 352 Suppl. I: 8-14Abstract Full Text Full Text PDF Google Scholar), and an increase in myocardial βARK1 activity (7Ungerer M. Parruti G. Bohm M. Puzicha M. DeBlasi A. Erdmann E. Lohse M.J. Circ. Res. 1994; 74: 206-213Crossref PubMed Scopus (252) Google Scholar). It remains controversial whether alterations in the βAR system are important in the pathogenesis of the failing heart. In this regard, we have recently reported the striking finding that cardiac overexpression of a βARK inhibitor prevents the development of cardiomyopathy in a genetic model of murine heart failure (8Rockman H.A. Chien K.R. Choi D.J. Iaccarino G. Hunter J.J. Ross Jr., J. Lefkowitz R.J. Koch W.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7000-7005Crossref PubMed Scopus (432) Google Scholar). Thus, abnormal βAR/G protein-coupling early in the development of the failing heart appears to be a critical event in the progressive nature of this disease (8Rockman H.A. Chien K.R. Choi D.J. Iaccarino G. Hunter J.J. Ross Jr., J. Lefkowitz R.J. Koch W.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7000-7005Crossref PubMed Scopus (432) Google Scholar). Calsequestrin (CSQ) is a 55-kDa high capacity Ca+2-binding protein located in the lumen of the junctional sarcoplasmic reticulum that forms a quaternary complex with junctin, triadin, and the ryanodine receptor, which are all required for the normal regulation of Ca2+ release by the ryanodine receptor (9Zhang L. Kelley J. Schmeisser G. Kobayashi Y.M. Jones L.R. J. Biol. Chem. 1997; 272: 23389-23397Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar). Recently, we and others have characterized the electrophysiological properties of transgenic mice with impaired Ca2+ release achieved through cardiac overexpression of CSQ (10Jones L.R. Suzuki Y.J. Wang W. Kobayashi Y.M. Ramesh V. Franzini-Armstrong C. Cleemann L. Morad M. J. Clin. Invest. 1998; 101: 1385-1393Crossref PubMed Scopus (247) Google Scholar, 11Sato Y. Ferguson D.G. Sako H. Dorn II, G.W. Kadambi V.J. Yatani A. Hoit B.D. Walsh R.A. Kranias E.G. J. Biol. Chem. 1998; 273: 28470-28477Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). CSQ-overexpressing transgenic mice showed markedly reduced Ca2+-induced Ca2+release (10Jones L.R. Suzuki Y.J. Wang W. Kobayashi Y.M. Ramesh V. Franzini-Armstrong C. Cleemann L. Morad M. J. Clin. Invest. 1998; 101: 1385-1393Crossref PubMed Scopus (247) Google Scholar, 11Sato Y. Ferguson D.G. Sako H. Dorn II, G.W. Kadambi V.J. Yatani A. Hoit B.D. Walsh R.A. Kranias E.G. J. Biol. Chem. 1998; 273: 28470-28477Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar) and frequency of Ca2+ sparks (10Jones L.R. Suzuki Y.J. Wang W. Kobayashi Y.M. Ramesh V. Franzini-Armstrong C. Cleemann L. Morad M. J. Clin. Invest. 1998; 101: 1385-1393Crossref PubMed Scopus (247) Google Scholar). Interestingly, CSQ overexpression was associated with myocyte hypertrophy, depressed cellular contractility, and induction of a fetal gene program. The purpose of this study was to determine whether defects in βAR signaling are associated with this mouse model of cellular contractile failure so as to better understand the cellular mechanisms involved in the initiation of pathological hypertrophy and heart failure. Transgenic mice overexpressing (CSQ) mice were generated as described previously (10Jones L.R. Suzuki Y.J. Wang W. Kobayashi Y.M. Ramesh V. Franzini-Armstrong C. Cleemann L. Morad M. J. Clin. Invest. 1998; 101: 1385-1393Crossref PubMed Scopus (247) Google Scholar). Briefly, full-length canine cardiac CSQ cDNA was fused to the α-myosin heavy chain promoter to drive cardiac-targeted expression. Age-matched transgenic and wild-type littermates of either sex were used. The genotype was determined by polymerase chain reaction as described previously (10Jones L.R. Suzuki Y.J. Wang W. Kobayashi Y.M. Ramesh V. Franzini-Armstrong C. Cleemann L. Morad M. J. Clin. Invest. 1998; 101: 1385-1393Crossref PubMed Scopus (247) Google Scholar). The animals in this study were handled according to approved protocols and the animal welfare regulations of the University of North Carolina at Chapel Hill and the Indiana University. Echocardiography was performed in anesthetized mice (Avertin 2.5%, 14 μl/g intraperitoneally) using an ATL HDI 5000 echocardiograph (ATL Ultrasound, Bothell, WA) as described previously (8Rockman H.A. Chien K.R. Choi D.J. Iaccarino G. Hunter J.J. Ross Jr., J. Lefkowitz R.J. Koch W.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7000-7005Crossref PubMed Scopus (432) Google Scholar). Wild-type and CSQ mice at the age of 7 and 14 weeks were evaluated by noninvasive echocardiography followed by invasive hemodynamics. In a separate group of mice, serial echocardiograms were obtained in the same animals over a 5-week period of time with the initial study at 8.4 ± 0.4 weeks of age and a second study performed at 13.3 ± 0.4 weeks of age. The operator who performed and measured the echocardiograms was blinded to the genotype of the animals. The following parameters were measured: LVEDD; LVESD; % FS, calculated as (LVEDD − LVESD)/LVEDD × 100; SEPth; PWth, mVcfc, calculated as fractional shortening divided by ejection time multiplied by the square root of the R-R interval. Estimated echocardiographic LV mass (in mg) was calculated as ((LVEDD + SEPth + − × is the density of and for was for and for wall thickness. echocardiography, was performed in mice as described previously (8Rockman H.A. Chien K.R. Choi D.J. Iaccarino G. Hunter J.J. Ross Jr., J. Lefkowitz R.J. Koch W.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7000-7005Crossref PubMed Scopus (432) Google Scholar, Koch W.J. Hunter J.J. H.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). were anesthetized with a of and and to a high was the and the were on an and in at at and of of (8Rockman H.A. Chien K.R. Choi D.J. Iaccarino G. Hunter J.J. Ross Jr., J. Lefkowitz R.J. Koch W.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7000-7005Crossref PubMed Scopus (432) Google Scholar). were were and were and in for measured were heart LV systolic pressure, LV pressure, LV and LV were for In separate CSQ overexpressing animals at 14 weeks of heart rate was to the wild-type mice by and as a from a of was the and the a period of was at a rate of and parameters were as were by from 7- and mice in as described previously (8Rockman H.A. Chien K.R. Choi D.J. Iaccarino G. Hunter J.J. Ross Jr., J. Lefkowitz R.J. Koch W.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7000-7005Crossref PubMed Scopus (432) Google Scholar, Koch W.J. Hunter J.J. H.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Koch W.J. S.A. H.A. Circulation. PubMed Google Scholar, W.J. H.A. R.A. R.A. Lefkowitz R.J. Science. PubMed Scopus Google Scholar). βAR density was determined by of cardiac with a of and to W.J. H.A. R.A. R.A. Lefkowitz R.J. Science. PubMed Scopus Google Scholar). is of the in were in with of to were at for and over that were and in a were by square cyclase activity was performed on myocardial from 7- and mice (8Rockman H.A. Chien K.R. Choi D.J. Iaccarino G. Hunter J.J. Ross Jr., J. Lefkowitz R.J. Koch W.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7000-7005Crossref PubMed Scopus (432) Google Scholar, Koch W.J. Hunter J.J. H.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, W.J. H.A. R.A. R.A. Lefkowitz R.J. Science. PubMed Scopus Google Scholar). to of were for at with and was (8Rockman H.A. Chien K.R. Choi D.J. Iaccarino G. Hunter J.J. Ross Jr., J. Lefkowitz R.J. Koch W.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7000-7005Crossref PubMed Scopus (432) Google Scholar, Koch W.J. Hunter J.J. H.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, W.J. H.A. R.A. R.A. Lefkowitz R.J. Science. PubMed Scopus Google Scholar). activity was measured in myocardial using as an in as described previously Koch W.J. Hunter J.J. H.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Koch W.J. S.A. H.A. Circulation. PubMed Google Scholar, W.J. H.A. R.A. R.A. Lefkowitz R.J. Science. PubMed Scopus Google Scholar). of was with in of reaction and The were in for and with of and for at were in of protein and through was by and using a of myocardial levels of βARK1 was performed on following using a as described previously (8Rockman H.A. Chien K.R. Choi D.J. Iaccarino G. Hunter J.J. Ross Jr., J. Lefkowitz R.J. Koch W.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7000-7005Crossref PubMed Scopus (432) Google Scholar, Koch W.J. Hunter J.J. H.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, W.J. H.A. R.A. R.A. Lefkowitz R.J. Science. PubMed Scopus Google Scholar). The βARK1 protein was with the an the of βARK1 and of with was performed on LV obtained from 7- and 14-week CSQ and wild-type mice as described previously H.A. Ross Ross Jr., J. Chien K.R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). was by a of the was by to by and with were at for 1 and for at the of cDNA using were and were by are as mean ± To for in serial echocardiographic data and data between CSQ and wild-type mice, a analysis of was analysis with to in mean between the was with a between wild-type and CSQ mice at either 7 14 weeks of age for the chamber and echocardiographic was performed using echocardiography was used to LV chamber and cardiac in transgenic and wild-type mice. As in overexpression of CSQ in an early phenotype of chamber and increased wall that progressed to one of LV enlargement and cardiac By 16 weeks of age all mice echocardiographic data obtained in 7- and mice are in 7 weeks, CSQ mice showed mild chamber enlargement, mild reduction in % FS, and increased wall thickness. In at 14 weeks, cardiac enlargement and marked cardiac was with a reduction in wall to normal and parameters in 7- and CSQ-overexpressing ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± dP/dtmax ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± heart left ventricular heart left ventricular systolic left ventricular are as mean ± CSQ for either 7- 14-week mice CSQ CSQ for 14 weeks, in in a new heart left ventricular heart left ventricular systolic left ventricular are as mean ± CSQ for either 7- 14-week mice CSQ CSQ for 14 weeks, in In a separate group of CSQ and wild-type mice, serial echocardiography was data for echocardiographic parameters are for CSQ mice studied at 8.4 ± 0.4 weeks of age and at a echocardiographic study weeks the initial 7 of the CSQ mice normal LV chamber and systolic as by the normal and % early phenotype was associated with a significant increase in septal and posterior wall ± ± In over a period of weeks, all CSQ mice showed an increase in decrease in % and reduction in wall Thus, cardiac overexpression of CSQ to an initial phenotype of cardiac hypertrophy with a mild reduction in systolic that to cardiac enlargement and marked LV with premature In to the enlargement in chamber CSQ-overexpressing mice showed a progressive increase in LV mass as determined by serial Estimated LV mass of CSQ mice at was greater in wild-type mice ± ± the 5-week study change in LV mass was in wild-type a increase in the LV mass was in the CSQ-overexpressing mice at ± ± data are with the heart data obtained at following the study in the 7- and mice To determine whether in βAR responsiveness was altered in mice with CSQ cardiac catheterization was performed in 7- and 14-week CSQ and wild-type mice. 7 weeks of as measured by the first derivative of LV was reduced in the CSQ mice with wild-type mice In response to CSQ mice showed a markedly response as with the increase in LV dP/dtmax in wild-type mice assessed by LV was impaired and with Although LV systolic was reduced heart rate was in the CSQ mice at and with data show that in the of overt heart CSQ mice show marked abnormalities of βAR in Cardiac catheterization in 14-week CSQ mice showed a with markedly depressed and LV dP/dtmax impaired LV reduced LV systolic and heart rate with in data that CSQ overexpression is associated with a in βAR responsiveness that early in the of the cardiac phenotype and precede the development of LV enlargement and of LV contractile in response to βAR at 14 the at 14 weeks of cardiac catheterization and was performed as in and CSQ mice. LV LV LV systolic heart CSQ The of change between was significant for LV LV and heart heart rate can LV as measured by the LV in parameters were obtained in a separate group of 14-week CSQ animals that to heart rate to that of wild-type mice. heart rate to increase LV dP/dtmax in the CSQ mice in a significant To determine whether overexpression of CSQ to abnormalities in βAR we evaluated coupling in from of CSQ mice the 7- and 14-week both 7 and 14 weeks of total βAR density was reduced in CSQ with wild-type In to the decrease in βAR density, the of for was reduced in from both 7- and 14-week CSQ with The significant reduction in the number of high affinity is with a decreased of to the protein high affinity changes are W.J. H.A. R.A. R.A. Lefkowitz R.J. Science. PubMed Scopus Google Scholar). decrease in βAR density and % high affinity agonist was associated with a marked reduction in adenylyl cyclase activity in both the 7- and 14-week mouse a in βAR coupling data are with the in and indicate that cardiac overexpression of CSQ to of to the development of failure. βAR in human heart failure is associated with increased levels and activity of βARK1 (7Ungerer M. Parruti G. Bohm M. Puzicha M. DeBlasi A. Erdmann E. Lohse M.J. Circ. Res. 1994; 74: 206-213Crossref PubMed Scopus (252) Google Scholar, M. Bohm M. Erdmann E. Lohse M.J. Circulation. PubMed Scopus Google Scholar), a that and Thus, we measured activity and βARK1 protein levels in from of CSQ and wild-type mice. have previously that the βARK1 for all the activity in from mouse Koch W.J. Hunter J.J. H.A. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). βARK1 protein levels in myocardial from 7- and 14-week CSQ were determined by protein following of heart with a to As in and the of βARK1 protein was in the of the CSQ mice at both with wild-type mice. were used as a for myocardial with the increase in βARK1 protein significant in activity was in obtained from and 14-week CSQ mice with wild-type mice data that the abnormal coupling early in the progressive cardiac phenotype by CSQ overexpression is associated with increased βARK1 which to the marked of measured to cyclase analysis a marked increase in levels in CSQ at both 7 and 14 weeks with wild-type is with an induction of a fetal gene in response to Y. Ferguson D.G. Sako H. Dorn II, G.W. Kadambi V.J. Yatani A. Hoit B.D. Walsh R.A. Kranias E.G. J. Biol. Chem. 1998; 273: 28470-28477Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, H.A. Ross Ross Jr., J. Chien K.R. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The study that cardiac-targeted overexpression of CSQ in a cardiac phenotype characterized by marked LV hypertrophy and mild decrease in cardiac systolic which to LV enlargement, cardiac and reduction in myocardial wall thickness. phenotype is associated with a number of abnormalities in βAR which to the development of overt heart failure as by a decrease in total βAR density and % high affinity agonist binding, reduced and adenylyl cyclase activity, in βAR and the increase in βARK1 levels. CSQ is a Ca2+ protein located in the junctional sarcoplasmic reticulum which as the of the contractile Ca2+ in response to of the ryanodine receptor activation of the L-type in the in the CSQ-overexpressing mice revealed that CSQ is a protein is involved in the regulation of intracellular Ca2+ in heart (10Jones L.R. Suzuki Y.J. Wang W. Kobayashi Y.M. Ramesh V. Franzini-Armstrong C. Cleemann L. Morad M. J. Clin. Invest. 1998; 101: 1385-1393Crossref PubMed Scopus (247) Google Scholar). The data from this study that suppression of Ca2+ release by overexpression of a of molecular that the to progressive cardiac Interestingly, in this study we show that one of the signaling pathways to early in the time of this phenotype is the βAR In to the significant reduction in βAR density and % high affinity in the of CSQ mice, a marked of was by the severely depressed response to in and in cyclase that to the of in this model is the significant in βARK1 levels. Thus, to a for βAR in the pathogenesis of the failing heart (8Rockman H.A. Chien K.R. Choi D.J. Iaccarino G. Hunter J.J. Ross Jr., J. Lefkowitz R.J. Koch W.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7000-7005Crossref PubMed Scopus (432) Google Scholar). 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Ferguson D.G. Sako H. Dorn II, G.W. Kadambi V.J. Yatani A. Hoit B.D. Walsh R.A. Kranias E.G. J. Biol. Chem. 1998; 273: 28470-28477Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar). that through G protein-coupled are critical in the initiation of the program. in the progressive in cardiac that with Y. Hoit B.D. Walsh R.A. Dorn Circulation. 1998; PubMed Scopus Google Scholar). In this regard, we have recently an for the in the initiation of ventricular S.A. H.A. Iaccarino G. Lefkowitz R.J. Koch W.J. Science. 1998; PubMed Scopus Google Scholar). receptor signaling pathways are in the of transgenic mice with CSQ overexpression and progressive cardiomyopathy remains to be it is that CSQ mice as the initial LV hypertrophy, the that alterations in intracellular Ca2+ are important in the gene J. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Although mouse of cardiomyopathy have been Y. Hoit B.D. Walsh R.A. Dorn Circulation. 1998; PubMed Scopus Google J. 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Res. 1998; PubMed Google Scholar). the initial is LV hypertrophy and systolic which to LV enlargement and In this model of cardiac-targeted overexpression of CSQ a to to the transition from cardiac hypertrophy to heart failure. a that the of mouse with analysis of the cardiac phenotype the of the molecular involved in the development of cardiac hypertrophy and heart failure. for for with cyclase and binding, and J. Lefkowitz for βARK1 and the