This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Miyata, S. Articles by Leinwand, L. A. Search for Related Content PubMed PubMed Citation Articles by Miyata, S. Articles by Leinwand, L. A. Related Collections Contractile function Other myocardial biology Congestive Heart failure - basic studies

(Circulation Research. 2000;86:386.)
© 2000 American Heart Association, Inc.

Clinical Research

Myosin Heavy Chain Isoform Expression in the Failing and Nonfailing Human Heart

Setsuya Miyata, Wayne Minobe, Michael R. Bristow, Leslie A. Leinwand

From the Department of Molecular, Cellular and Developmental Biology (S.M., L.A.L.), University of Colorado (Boulder); and Division of Cardiology (W.M., M.B.), University of Colorado Health Science Center (Denver).

Correspondence to Dr Leslie A. Leinwand, Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Campus Box 347, Boulder, CO 80309-0347. E-mail Leslie.Leinwand{at}colorado.edu

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Abstract—In the heart, the relative proportions of the 2 forms of the motor protein myosin heavy chain (MyHC) have been shown to be affected by a wide variety of pathological and physiological stimuli. Hearts that express the faster MyHC motor protein, , produce more power than those expressing the slower MyHC motor protein, ß, leading to the hypothesis that MyHC isoforms play a major role in the determination of cardiac contractility. We showed previously that a significant amount of MyHC mRNA is expressed in nonfailing human ventricular myocardium and that MyHC mRNA expression is decreased 15-fold in end-stage failing left ventricles. In the present study, we determined the MyHC protein isoform content of human heart samples of known MyHC mRNA composition. We demonstrate that MyHC protein was easily detectable in 12 nonfailing hearts. MyHC protein represented 7.2±3.2% of total MyHC protein (compared with 35% of the MyHC mRNA), suggesting that translational regulation may be operative; in contrast, there was effectively no detectable MyHC protein in the left ventricles of 10 end-stage failing human hearts.

Key Words: myosin • heart failure • isoforms

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
In conjunction with 2 pairs of nonidentical light chains, 2 myosin heavy chain (MyHCs) constitute the functional myosin motor molecule. Two isoforms of MyHC ( and ß) are expressed in mammalian heart. Myosin consisting of MyHC has a higher ATPase activity than myosin composed of ßMyHC,¹ and in the rodent heart, contractile velocity correlates with the relative amount of each MyHC. Hearts expressing MyHC have more rapid contractile velocity than hearts expressing ßMyHC, which allows greater economy in force generation because the tension-time integral for force per cross-bridge cycle is greater.^{2 3} The MyHC composition of the ventricular myocardium of rodents has been reported to be >90% MyHC,^{4 5 6} whereas that of humans has been reported to be >95% ßMyHC.^{7 8 9 10 11 12 13} In the rodent heart, thyroid hormone elevation and exercise have been shown to increase MyHC, whereas thyroid depletion, aging, cardiomyopathy, and pressure overload have been shown to increase ßMyHC (see Swynghedauw¹⁴ ). Because the normal human heart was previously thought to be entirely ßMyHC,^{7 8 9 10 11 12 13} stimuli that might induce isoform shifts toward ßMyHC in human heart disease were thought to be irrelevant.

The MyHC composition of human heart was originally investigated with immunohistochemistry, because of the difficulty in electrophoretic separation of the human MyHC and ßMyHC,⁹ or by peptide mapping.^{7 10} Immunohistochemistry can show the spatial expression of each isoform, but it is not quantitative because 2 different antibodies cannot be directly compared.^{15 16} The results of immunohistochemical analysis were quite varied, with reports ranging from <5% to 88% of myocytes expressing MyHC.^{8 11 12} We showed that MyHC mRNA was expressed at considerable levels in the nonfailing human left ventricles (LVs) and was substantially decreased in end-stage failing human LVs.^{17 18} The proportion of total MyHC mRNA that is MyHC mRNA was 30% in nonfailing LVs and was reduced by 15-fold, to 2%, in end-stage LVs.

Because of the potential functional significance of altered MyHC composition in contractility and to gain insight into the molecular mechanisms of changes in gene expression in heart failure, we quantified MyHC and ßMyHC proteins in human nonfailing and failing LVs according to a recently reported gel electrophoretic method.¹⁹ We demonstrate that MyHC protein is detectable in nonfailing LVs but is virtually undetectable in failing LVs.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Patients from whom hearts were provided through the Colorado Transplant Program are described in Tables 1 and 2.¹⁷ LVs were obtained from 12 control organ donor candidates (5 men and 7 women, mean age 36.8±16.9 years) and 10 patients undergoing heart transplantation (8 men and 2 women, mean age 44.9±19.3 years).

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics and MyHC cDNA and Protein Ratios of 12 Organ Donors Without a Heart Failure History

View this table: [in this window] [in a new window]   Table 2. Clinical Characteristics and MyHC cDNA and Protein Ratios of 10 Patients With End-Stage Heart Failure

RNA was extracted and analyzed with quantitative polymerase chain reaction as previously described and reported.^{17 18}

Samples for protein gel electrophoresis (15 to 200 mg) were prepared as described by Caforio et al²⁰ from tissue that had no visible fat and no connective tissue. Briefly, samples were homogenized in low-salt buffer (20 mmol/L KCl, 2 mmol/L KH₂PO₄, 1 mmol/L EGTA, pH 6.8, 1 mmol/L PMSF, 100 µL N,N-dimethyl formamide). The samples were then centrifuged at 5000 rpm for 10 minutes at 4°C in a JA-17 rotor (Beckman Instruments). Pellets were suspended in high-salt buffer (40 mmol/L Na₄P₂O₇, 1 mmol/L MgCl₂, 1 mmol/L EGTA, pH 9.5) and then centrifuged at 15 000 rpm for 30 minutes at 4°C. Laemmli’s buffer was added to each sample, and then each sample was boiled.²¹ The preparation and composition of the gel were carried out as described by Reiser and Kline.¹⁹ Gel samples (0.25 to 1 µg) were loaded in a 3-µL volume onto 15-well gels. The stacking and separating gels (0.75 mm thick) consisted of 4% and 8% acrylamide, respectively; the stacking gels included 5% glycerol. The gels were run in a Hoeffer Scientific SE600 instrument at 5°C. The gels were run at a constant voltage of 200 V for 30 hours. The gels were fixed and silver stained as described in Blough et al.²² A gel documentation system (Bio-Rad) was used to scan the stained gels. The abundance of MyHC and ßMyHC was determined with quantitative reverse transcription–polymerase chain reaction as previously described.^{17 18} Protein samples were subjected to electrophoresis as described earlier and transferred to 0.2-µm nitrocellulose. The blots were blocked in 10% nonfat dry milk in PBS for 2 hours at room temperature. Blots were incubated with a monoclonal antibody against sarcomeric MyHC (F59)²³ or F88.12F8 (Alexis Biochemicals) at a dilution of 1:500 or 1:5000, respectively, in 5% BSA overnight at 4°C. After primary antibody incubations, 3 washes in PBS were followed by an incubation in the secondary antibody, peroxidase-conjugated goat anti-mouse IgG (Jackson Laboratories) diluted 1:5000 in 10% nonfat dry milk in PBS for 2 hours at room temperature. The blots were then washed 3 times in 0.05% NP-40/PBS. Immunoreactive bands were visualized by using the Renaissance Western Blot Chemiluminescence Reagent (NEN Life Sciences).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
The goals of the present study were to determine the amount of MyHC protein in the nonfailing and failing human hearts and to determine the relationship between MyHC mRNA and protein levels. The clinical characteristics and the MyHC mRNA content of the patients analyzed in the present study are shown in Tables 1 and 2. The range of MyHC mRNA was 10.8% to 55% in nonfailing LVs and 0% to 8.8% in failing LVs. To identify MyHC protein, immunoblot analysis was carried out with a monoclonal antibody specific to MyHC protein.¹⁵ To quantify the proportion of MyHC protein, an electrophoretic separation protocol was used, followed by silver staining and densitometry. Figure 1 is an immunoblot performed on a high-resolution gel that separates MyHC and ßMyHC proteins. The gel was probed with pansarcomeric MyHC antibody F59²³ (top) and an MyHC-specific antibody (bottom).¹⁵ Lane 1 represents rabbit skeletal MyHC, used as a control. It was recognized by the pansarcomeric MyHC antibody but not by the MyHC-specific antibody. MyHC was prominently expressed in a right atrial sample (lane 2), as expected.²⁴ As an additional control, the right atrial sample was mixed 1:1 with an LV sample (lane 3). Two bands were recognized by the pansarcomeric antibody, but only the top band was recognized by the MyHC antibody. MyHC was easily detectable in 2 nonfailing LVs (lanes 4 and 5). These results demonstrate that human MyHC and ßMyHC can be resolved into 2 bands and that the slower migrating species is MyHC. However, this immunoblot analysis does not provide quantitative information about MyHC levels. For that purpose, a high-resolution gel was run, silver stained, and subjected to laser scanning densitometry. Figure 2 is a representative silver-stained gel of MyHC from nonfailing and failing LVs. The results of the scan are presented in Tables 1 and 2. The RA (right atrial) sample contained 86% MyHC and 14% ßMyHC and served as a positive control²⁴ (Figure 2). MyHC protein was detected in all 12 nonfailing LVs and corresponded to 7.2±3.2% of total MyHC ([mean±SD] range 1.2% to 13%). One patient’s heart that was originally included in the nonfailing group had no MyHC protein. However, when the clinical characteristics were examined in greater detail, it was found that this patient had a history of myocardial infarction and exhibited an anterior wall motion abnormality; data on this patient’s tissue were subsequently eliminated from the analysis. However, the finding of no MyHC protein in a setting of LV dysfunction suggests that changes in cardiac MyHC expression can precede the development of overt myocardial failure. MyHC protein was barely detectable (0.75%) in 1 of 10 failing LVs, from an 18-year-old patient with idiopathic dilated cardiomyopathy and with 8.8% MyHC mRNA (Figure 2). No MyHC protein was detected in the remaining 9 failing LV samples.

View larger version (44K): [in this window] [in a new window]   Figure 1. Immunodetection of MyHC and ßMyHC after high-resolution gel electrophoresis. Top, Probed with F59, which recognizes all sarcomeric MyHCs.23 Bottom, Probed with F88.12.F8, which is specific to MyHC.15 Lane 1 indicates rabbit skeletal MyHC; lane 2, human right atrial sample; lane 3, a 1:1 mixture of right atrium and LV; lane 4, NFH-1; and lane 5, NFH-3.

View larger version (19K): [in this window] [in a new window]   Figure 2. Separation of human MyHC and ßMyHC proteins. Protein samples of human left ventricles were resolved on an SDS–8% polyacrylamide gel. The gel was fixed and silver stained as described previously.19 The relative amounts of MyHC and ßMyHC protein in nonfailing and failing heart LVs were determined with scanning densitometry and are presented in Tables 1 and 2.

Investigation into the molecular and cellular mechanisms of heart failure has provided some insight into changes in gene expression that could contribute to contractile dysfunction. Given the potential functional significance of MyHC protein in the myocardium, it was important to determine whether protein was also present. MyHC protein was detected all 12 nonfailing LVs but was undetectable in 9 of 10 failing LVs and barely detectable in the remaining failing LV. Interestingly, in all nonfailing LVs, there was more MyHC mRNA than protein (see Table 1). Discordance between MyHC mRNA and protein has been demonstrated in several reports and systems.²⁵ For example, electrical stimulation of adult cardiac myocyte contraction accelerates MyHC synthesis by increasing the rate of translation initiation. This occurs in the absence of an increase in mRNA abundance.²⁶ After 7 days of ascending aortic constriction, ßMyHC protein increases from 5% to 31% of total MyHC in the absence of changes in mRNA abundance.²⁷ Finally, contractile arrest of cardiac myocytes has been shown to inhibit MyHC synthesis and to decelerate MyHC degradation.²⁸ Protein synthesis in the heart is regulated by changes in efficiency and capacity and has been shown to vary widely depending on the stimulus.^{29 30 31} Before drawing firm conclusions about the degree of discordance between mRNA and protein, 1 limitation of the silver-staining approach should be noted: in samples with very low amounts of MyHC, the ßMyHC band may obscure a faint MyHC band. To complement the approach used here and to be able to determine the absolute quantities of and ßMyHC, we are in the process of developing ELISAs.

One question that arises from these observations is whether a relatively small amount of MyHC is capable of changing the contractile properties of the heart. Thus far, the cases in which shifts in myosin composition have been studied have generally been at end points where the shift has been quite large. The impact of small shifts such as those described here have not yet been reported. However, with the assumption of a 3-fold difference in the velocity of shortening in muscles expressing the and ß isoforms, the decrease in MyHC from 7.5% to <0.1% could theoretically reduce systolic function by 12.5%, although the direct relationship to velocity of contraction would have to be tested directly. In support of this hypothesis, we recently used transgenesis to express ßMyHC in the adult mouse heart, which normally expresses exclusively MyHC. When only 12% of the total MyHC is ßMyHC, there is a significant decrease in systolic function and Ca⁺²-activated myofibrillar ATPase activity.³² However, in vitro biochemical mixing experiments with varying proportions of and ß myosin show that ß myosin can have a "slowing" effect on myosin, suggesting that the impact of myosin changes in the intact heart may not reflect the behavior of purified molecules in solution.³³ The sensitivity of the cardiac sarcomere to alterations in MyHC has been emphasized by the discovery of >50 alleles of the ßMyHC gene found in patients with hypertrophic cardiomyopathy (see Bonne et al³⁴ ). Most of these alleles have mutations in the motor domain, and in vitro biochemical studies have shown that the motor activity is impaired in at least 3 different alleles.^{35 36 37} Somewhat surprisingly, the functional differences in the mutant alleles are less than the difference between wild-type MyHC and ßMyHC.³⁷ Further investigation is required to understand the relationship of decreased myosin motor activity and the pathogenesis of hypertrophic cardiomyopathy and heart failure.

In summary, we separated human MyHC and ßMyHC proteins through electrophoresis and quantified the relative amounts of MyHC and ßMyHC in nonfailing and failing LVs. MyHC is detectable in nonfailing LVs but effectively undetectable in failing LVs. Future experiments will be directed toward a determination of the mechanism of MyHC mRNA decrease and the relevance of changes in MyHC gene expression to human cardiac function.

	Acknowledgments

 
This work was supported by NIH grant HL-50560 (to Dr Leinwand) and an American Heart Association, Colorado-Wyoming Affiliate, fellowship award (to Dr Miyata. The authors would like to thank Jill Jones for manuscript preparation and Kurt Haubold for figure preparation.

	Footnotes

 
This manuscript was sent to Harry A. Fozzard, Consulting Editor, for review by expert referees, editorial decision, and final disposition.

Received March 18, 1999; accepted July 7, 1999.

	References

Top Abstract Introduction Materials and Methods Results and Discussion References

 

1. Pope B, Hoh JFY, Weeds A. The ATPase activities of rat cardiac myosin isozymes. FEBS Lett. 1980;118:205–208.[Medline] [Order article via Infotrieve]
2. Alpert NR, Mulieri LA. Increased myothermal economy of isometric force generation in compensated cardiac hypertrophy induced by pulmonary artery constriction in the rabbit. Circ Res. 1982;50:491–500.[Free Full Text]
3. Holubarsch CH, Goulette RP, Litten RZ, Martin BJ, Mulieri LA, Alpert NR. The economy force development, myosin isozyme pattern and myofibrillar ATPase activity in normal and hyperthyroid rat myocardium. Circ Res. 1985;56:78–86.[Abstract/Free Full Text]
4. Lompre AM, Schwartz K, d’Albis A, Lacombe G, Thiem NV, Swynghedauw B. Myosin isozyme re-distribution in chronic heart over-load. Nature. 1979;282:105–107.[Medline] [Order article via Infotrieve]
5. Mercardier JJ, Lompre AM, Winewsky C, Samuel JL, Bercovici J, Swynghedauw B, Schwartz K. Myosin isozyme changes in several model of rat cardiac hypertrophy. Circ Res. 1981;49:525–532.[Abstract/Free Full Text]
6. Peng HB, Wolosewick JJ, Cheng P-C. The development of myofibrils in cultured muscle cells: a whole mount and thin-section electron microscopic study. Dev Biol. 1981;88:121–136.[Medline] [Order article via Infotrieve]
7. Schier JJ, Adelstein R. Structural and enzymatic comparison of human cardiac muscle myosins isolated from infants, adult, and patients with hypertrophic cardiomyopathy. J Clin Invest. 1982;69:816–825.
8. Gorza L, Mercadier JJ, Schwartz K, Thornell LE, Sartore S, Schiaffino S. Myosin types in the human heart: an immunofluorescence study of normal and hypertrophied atrial and ventricular myocardium. Circ Res. 1984;54:694–702.[Abstract/Free Full Text]
9. Mercadier JJ, Bouveret P, Gorza L, Schiaffino S, Clark WA, Zak R, Swynghedauw B, Schwartz K. Myosin isozymes in normal and hypertrophied human ventricle myocardium. Circ Res. 1983;53:52–62.[Abstract/Free Full Text]
10. Hirtel HO, Tuchschmid CR, Schneider J, Krayenbuehl HP, Schaub MC. Relationship between myosin isozyme composition, hemodynamics, and myocardial structure in various forms of human cardiac hypertrophy. Circ Res. 1985;57:729–740.[Abstract/Free Full Text]
11. Schiaffino S, Gorza L, Saggin L, Valfre C, Sartore S. Myosin changes in hypertrophied human atrial and ventricular myocardium: a correlated immunofluorescence and quantitative immunochemical study on serial cryosections. Eur Heart J. 1984;5:95–102.[Free Full Text]
12. Bouvagnet P, Marirhofer H, Leger JO, Puech P, Leger JJ. Distribution pattern of and ß myosin in normal and diseased human ventricular myocardium. Basic Res Cardiol. 1989;84:91–102.[Medline] [Order article via Infotrieve]
13. Tsuchimochi H, Sugi M, Kuro-o S, Ueda F, Takaku F, Furuta S, Shirai T, Yazaki Y. Isozymic change in myosin of human atrial myocardium induced by overload: immunohistochemical study using monoclonal antibodies. J Clin Invest. 1984;74:662–665.
14. Swynghedauw B. Developmental and functional adaptation of contractile proteins in cardiac and skeletal muscles. Physiol Rev. 1986;66:710–730.[Abstract/Free Full Text]
15. Dechesne C, Leger J, Bouvagnet P, Claviez M, Leger JJ. Fractionation and characterization of two molecular variants of myosin from adult human atrium. J Mol Cell Cardiol. 1985;17:753–756.[Medline] [Order article via Infotrieve]
16. Leger J, Bouvagnet P, Pau B, Roncucci R, Leger JJ. Levels of ventricular myosin fragments in human sera after myocardial infarction, determined with monoclonal antibodies to myosin heavy chain. Eur J Clin Invest. 1985;15:422–429.[Medline] [Order article via Infotrieve]
17. Nakao K, Minobe W, Roden R, Bristow MR, Leinwand LA. Myosin heavy chain gene expression in human heart failure. J Clin Invest. 1997;100:2362–2370.[Medline] [Order article via Infotrieve]
18. Lowes BD, Minobe W, Abraham WT, Rizeq MN, Bohlmeyer TJ, Quaife RA, Roden RL, Ducher DL, Robertson AD, Voelkel NF, Badesch DB, Groves BM, Gilbert EM, Bristow MR. Changes in gene expression in the intact human heart: downregulation of myosin heavy chain in hypertrophed, failing ventricular myocardium. J Clin Invest. 1997;100:2315–2324.[Medline] [Order article via Infotrieve]
19. Reiser PJ, Kline WO. Electrophoretic separation and quantitation of cardiac myosin heavy chain isoform in eight mammalian species. Am J Physiol. 1998;274(3 pt 2):H1048–H1058.
20. Caforio AL, Grazzini M, Mann JM, Keeling PJ, Bottazzo GF, McKenna WJ, Schiaffino S. Identification of - and ß-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy. Circulation. 1992;85:1734–1742.[Abstract/Free Full Text]
21. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970;237:680–685.
22. Blough ER, Rennie ER, Zhang F, Reiser PJ. Enhanced electrophoretic separation and resolution of myosin heavy chain in mammalian and avian skeletal muscles. Anal Biochem. 1996;233:31–35.[Medline] [Order article via Infotrieve]
23. Miller JB, Teal SB, Stockdale FE. Evolutionarily conserved sequences of striated muscle myosin heavy chain isoforms: epitope mapping by cDNA expression. J Biol Chem. 1989;264:13122–13130.[Abstract/Free Full Text]
24. Bouvagnet P, Leger J, Pons F, Dechesne C, Leger J. Fiber types and myosin types in human atrial and ventricular myocardium. Circ Res. 1984;55:794–804.[Abstract/Free Full Text]
25. Delcayre C, Klug D, Nguyen VT, Mouas C, Swynghedauw B. Aortic perfusion pressure as early determinant of ß-isomyosin expression in perfused hearts. Am J Physiol. 1992;263:H1537–H1545.[Abstract/Free Full Text]
26. Ivester CT, Tuxworth WJ, Cooper G VI, McDermont PJ. Contraction accelerates myosin heavy chain synthesis rate in adult cardiocytes by an increases in the rate of translational initiation. J Biol Chem. 1995;270:21950–21957.[Abstract/Free Full Text]
27. Weisner RJ, Ehmke H, Faulhaber J, Zak R, Rvegg JC. Dissociation of left ventricular hypertrophy, ß myosin heavy chain gene expression and myosin isoform switch in rats after ascending aortic construction. Circulation. 1997;95:1253–1259.[Abstract/Free Full Text]
28. Samarel A, Spagia M, Maloney V, Kamal S, Engelmann GL. Contractile arrest accelerates myosin heavy chain degradation in neonatal rat heart cells. Am J Physiol. 1992;263:C642–C652.[Abstract/Free Full Text]
29. Byron K, Puglisi J, Holda J, Elde D, Samarel A. Myosin heavy chain turnover in cultured neonatal rat heart cells: effects of (Ca⁺²)i and contractile activity. Am J Physiol. 1996;271:1447–1456.
30. Morgan HE, Gordon EE, Kira Y, Chura BHL, Russo LA, Peterson CJ, McDermont PJ, Watson PA. Biochemical mechanisms of cardiac hypertrophy. Annu Rev Physiol. 1987;49:533–543.[Medline] [Order article via Infotrieve]
31. Nagai R, Low RB, Stirewalt WS, Alpert NR, Litten RZ. Efficiency and capacity of protein synthesis are increased in pressure overload cardiac hypertrophy. Ann Physiol. 1988;255:H325–H328.
32. Tardiff JC, Hewett TE, Factor SM, Vikstrom KL, Robbins J, Leinwand LA. Expression of the ß(slow) isoform of the MHC in the adult mouse heart causes dominant-negative functional effects. Am J Physiol. In press.
33. Harris DE, Work SS, Wright RK, Alpert NR, Warshaw DM. Smooth, cardiac and skeletal muscle myosin force and motor generation is assessed by cross-bridge mechanical interactions in vitro. J Muscle Res Cell Motil. 1994;15:11–19.[Medline] [Order article via Infotrieve]
34. Bonne G, Carrier L, Richard P, Hainque B, Schwartz K. Familial hypertrophic cardiomyopathy: from mutations to functional defects. Circ Res. 1998;83:580–593.[Abstract/Free Full Text]
35. Cuda G, Fananapazir L, Epstein ND, Sellers JR. The in vitro motility activity of ß-cardiac myosin heavy chain depends on the nature of the ß myosin heavy chain gene mutation in hypertrophic cardiomyopathy. J Muscle Res Cell Motil. 1997;18:275–283.[Medline] [Order article via Infotrieve]
36. Sata M, Ikebe M. Functional analysis of the mutations in the human ß-cardiac myosin that are responsible for familial hypertrophic cardiomyopathy. J Clin Invest. 1996;98:2866–2873.[Medline] [Order article via Infotrieve]
37. Roopnarine O, Leinwand L. Functional analysis of myosin mutations that cause familial hypertrophic cardiomyopathy. Biophys J. 1998;75:3023–3030.[Abstract/Free Full Text]

This article has been cited by other articles:

				E. Bovill, S. Westaby, S. Reji, R. Sayeed, A. Crisp, and T. Shaw Induction by left ventricular overload and left ventricular failure of the human Jumonji gene (JARID2) encoding a protein that regulates transcription and reexpression of a protective fetal program J. Thorac. Cardiovasc. Surg., September 1, 2008; 136(3): 709 - 716. [Abstract] [Full Text] [PDF]

				J. A. Hill and E. N. Olson Cardiac Plasticity N. Engl. J. Med., March 27, 2008; 358(13): 1370 - 1380. [Full Text] [PDF]

				J. B. Pillai, M. Chen, S. B. Rajamohan, S. Samant, V. B. Pillai, M. Gupta, and M. P. Gupta Activation of SIRT1, a class III histone deacetylase, contributes to fructose feeding-mediated induction of the {alpha}-myosin heavy chain expression Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1388 - H1397. [Abstract] [Full Text] [PDF]

				N. Hamdani, V. Kooij, S. van Dijk, D. Merkus, W. J. Paulus, C. d. Remedios, D. J. Duncker, G. J.M. Stienen, and J. van der Velden Sarcomeric dysfunction in heart failure Cardiovasc Res, March 1, 2008; 77(4): 649 - 658. [Abstract] [Full Text] [PDF]

				L. M. Hanft, F. S. Korte, and K. S. McDonald Cardiac function and modulation of sarcomeric function by length Cardiovasc Res, March 1, 2008; 77(4): 627 - 636. [Abstract] [Full Text] [PDF]

				J. G. Edwards Cardiac MHC gene expression: more complexity and a step forward Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H14 - H15. [Full Text] [PDF]

				S. G. Haworth The cell and molecular biology of right ventricular dysfunction in pulmonary hypertension Eur. Heart J. Suppl., December 1, 2007; 9(suppl_H): H10 - H16. [Abstract] [Full Text] [PDF]

				M. Krenz, S. Sadayappan, H. E. Osinska, J. A. Henry, S. Beck, D. M. Warshaw, and J. Robbins Distribution and Structure-Function Relationship of Myosin Heavy Chain Isoforms in the Adult Mouse Heart J. Biol. Chem., August 17, 2007; 282(33): 24057 - 24064. [Abstract] [Full Text] [PDF]

				C.-K. Du, S. Morimoto, K. Nishii, R. Minakami, M. Ohta, N. Tadano, Q.-W. Lu, Y.-Y. Wang, D.-Y. Zhan, M. Mochizuki, et al. Knock-In Mouse Model of Dilated Cardiomyopathy Caused by Troponin Mutation Circ. Res., July 20, 2007; 101(2): 185 - 194. [Abstract] [Full Text] [PDF]

				M. C. G. Daniels, T. Naya, V. L. M. Rundell, and P. P. de Tombe Development of contractile dysfunction in rat heart failure: hierarchy of cellular events Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R284 - R292. [Abstract] [Full Text] [PDF]

				F. S. Korte and K. S. McDonald Sarcomere length dependence of rat skinned cardiac myocyte mechanical properties: dependence on myosin heavy chain J. Physiol., June 1, 2007; 581(2): 725 - 739. [Abstract] [Full Text] [PDF]

				E. van Rooij, L. B. Sutherland, X. Qi, J. A. Richardson, J. Hill, and E. N. Olson Control of Stress-Dependent Cardiac Growth and Gene Expression by a MicroRNA Science, April 27, 2007; 316(5824): 575 - 579. [Abstract] [Full Text] [PDF]

				T. J. Herron, R. Vandenboom, E. Fomicheva, L. Mundada, T. Edwards, and J. M. Metzger Calcium-Independent Negative Inotropy by {beta}-Myosin Heavy Chain Gene Transfer in Cardiac Myocytes Circ. Res., April 27, 2007; 100(8): 1182 - 1190. [Abstract] [Full Text] [PDF]

				J. E. Stelzer, S. L. Brickson, M. R. Locher, and R. L. Moss Role of myosin heavy chain composition in the stretch activation response of rat myocardium J. Physiol., February 15, 2007; 579(1): 161 - 173. [Abstract] [Full Text] [PDF]

				B. Schoffstall, N. M. Brunet, S. Williams, V. F. Miller, A. T. Barnes, F. Wang, L. A. Compton, L. A. McFadden, D. W. Taylor, M. Seavy, et al. Ca2+ sensitivity of regulated cardiac thin filament sliding does not depend on myosin isoform J. Physiol., December 15, 2006; 577(3): 935 - 944. [Abstract] [Full Text] [PDF]

				M. L. Tschirgi, I. Rajapakse, and M. Chandra Functional consequence of mutation in rat cardiac troponin T is affected differently by myosin heavy chain isoforms J. Physiol., July 1, 2006; 574(1): 263 - 273. [Abstract] [Full Text] [PDF]

				Y. Kong, P. Tannous, G. Lu, K. Berenji, B. A. Rothermel, E. N. Olson, and J. A. Hill Suppression of Class I and II Histone Deacetylases Blunts Pressure-Overload Cardiac Hypertrophy Circulation, June 6, 2006; 113(22): 2579 - 2588. [Abstract] [Full Text] [PDF]

				W. Xing, T.-C. Zhang, D. Cao, Z. Wang, C. L. Antos, S. Li, Y. Wang, E. N. Olson, and D.-Z. Wang Myocardin Induces Cardiomyocyte Hypertrophy Circ. Res., April 28, 2006; 98(8): 1089 - 1097. [Abstract] [Full Text] [PDF]

				C. Perrino and H. A. Rockman GATA4 and the Two Sides of Gene Expression Reprogramming Circ. Res., March 31, 2006; 98(6): 715 - 716. [Full Text] [PDF]

				K. W. Chaudhary, N. X. Barrezueta, M. B. Bauchmann, A. J. Milici, G. Beckius, D. B. Stedman, J. E. Hambor, W. L. Blake, J. D. McNeish, A. Bahinski, et al. Embryonic Stem Cells in Predictive Cardiotoxicity: Laser Capture Microscopy Enables Assay Development Toxicol. Sci., March 1, 2006; 90(1): 149 - 158. [Abstract] [Full Text] [PDF]

				A. Kenessey, E. A. Sullivan, and K. Ojamaa Nuclear localization of protein kinase C-{alpha} induces thyroid hormone receptor-{alpha}1 expression in the cardiomyocyte Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H381 - H389. [Abstract] [Full Text] [PDF]

				C. A. Emter, S. A. McCune, G. C. Sparagna, M. J. Radin, and R. L. Moore Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2030 - H2038. [Abstract] [Full Text] [PDF]

				J. A. Kuzman, T. A. Thomas, K. A. Vogelsang, S. Said, B. E. Anderson, and A. M. Gerdes Effects of induced hyperthyroidism in normal and cardiomyopathic hamsters J Appl Physiol, October 1, 2005; 99(4): 1428 - 1433. [Abstract] [Full Text] [PDF]

				F. S. Korte, T. J. Herron, M. J. Rovetto, and K. S. McDonald Power output is linearly related to MyHC content in rat skinned myocytes and isolated working hearts Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H801 - H812. [Abstract] [Full Text] [PDF]

				E. Carniel, M. R.G. Taylor, G. Sinagra, A. Di Lenarda, L. Ku, P. R. Fain, M. M. Boucek, J. Cavanaugh, S. Miocic, D. Slavov, et al. {alpha}-Myosin Heavy Chain: A Sarcomeric Gene Associated With Dilated and Hypertrophic Phenotypes of Cardiomyopathy Circulation, July 5, 2005; 112(1): 54 - 59. [Abstract] [Full Text] [PDF]

				D. Fraccarollo, P. Galuppo, I. Schmidt, G. Ertl, and J. Bauersachs Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction Cardiovasc Res, July 1, 2005; 67(1): 97 - 105. [Abstract] [Full Text] [PDF]

				X.-M. Gao, H. Kiriazis, X.-L. Moore, X.-H. Feng, K. Sheppard, A. Dart, and X.-J. Du Regression of pressure overload-induced left ventricular hypertrophy in mice Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2702 - H2707. [Abstract] [Full Text] [PDF]

				E. Vellaichamy, M. L. Khurana, J. Fink, and K. N. Pandey Involvement of the NF-{kappa}B/Matrix Metalloproteinase Pathway in Cardiac Fibrosis of Mice Lacking Guanylyl Cyclase/Natriuretic Peptide Receptor A J. Biol. Chem., May 13, 2005; 280(19): 19230 - 19242. [Abstract] [Full Text] [PDF]

				A.J. Marian On Mice, Rabbits, and Human Heart Failure Circulation, May 10, 2005; 111(18): 2276 - 2279. [Full Text] [PDF]

J. James, L. Martin, M. Krenz, C. Quatman, F. Jones, R. Klevitsky, J. Gulick, and J. Robbins Forced Expression