Passive stiffness changes caused by upregulation of compliant titin isoforms in human dilated cardiomyopathy hearts
Abstract
In the pathogenesis of dilated cardiomyopathy, cytoskeletal proteins play an important role. In this study, we analyzed titin expression in left ventricles of 19 control human donors and 9 severely diseased (nonischemic) dilated cardiomyopathy (DCM) transplant-patients, using gel-electrophoresis, immunoblotting, and quantitative RT-PCR. Both human-heart groups coexpressed smaller (≈3 MDa) N2B-isoform and longer (3.20 to 3.35 MDa) N2BA-isoforms, but the average N2BA:N2B-protein ratio was shifted from ≈30:70 in controls to 42:58 in DCM hearts, due mainly to increased expression of N2BA-isoforms >3.30 MDa. Titin per unit tissue was decreased in some DCM hearts. The titin-binding protein obscurin also underwent isoform-shifting in DCM. Quantitative RT-PCR revealed a 47% reduction in total-titin mRNA levels in DCM compared with control hearts, but no differences in N2B, all-N2BA, and individual-N2BA transcripts. The reduction in total-titin transcripts followed from a decreased area occupied by myocytes and increased connective tissue in DCM hearts, as detected by histological analysis. Force measurements on isolated cardiomyofibrils showed that sarcomeric passive tension was reduced on average by 25% to 30% in DCM, a reduction readily predictable with a model of wormlike-chain titin elasticity. Passive-tension measurements on human-heart fiber bundles, before and after titin proteolysis, revealed a much-reduced relative contribution of titin to total passive stiffness in DCM. Results suggested that the titin-isoform shift in DCM depresses the proportion of titin-based stiffness by ≈10%. We conclude that a lower-than-normal proportion of titin-based stiffness in end-stage failing hearts results partly from loss of titin and increased fibrosis, partly from titin-isoform shift. The titin-isoform shift may be beneficial for myocardial diastolic function, but could impair the contractile performance in systole.
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Human ventricles express both compliant N2BA and stiff N2B titin isoforms with a relative N2BA:N2B ratio of ~0.4-1.2.
“Human ventricles express both compliant N2BA and stiff N2B titin isoforms with a relative N2BA:N2B ratio of ~0.4–1.2”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Makarenko, et al., 2004
Swine express more N2BA isoform (N2BA:N2B ratio 1-1.5) than humans (ratio 0.4-1.2).
“the swine expresses more N2BA isoform (N2BA:N2B ratio of 1–1.5) than humans (N2BA:N2B ratio of 0.4–1.2) (Cazorla, et al., 2000; Chung, et al., 2011; Makarenko, et al., 2004; Nagueh, et al., 2004).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Makarenko, et al., 2004
One report concluded that swine not only expressed more N2BA than humans, but the N2BA:N2B ratio was more similar to dilated human cardiomyopathy, a condition where N2BA expression is upregulated.
“one of these reports (Chung, et al., 2011) concluded that not only swine expressed more N2BA than humans, but additionally the N2BA:N2B ratio of this animal model was more similar to dilated human cardiomyopathy, a condition were N2BA expression is upregulated (Makarenko, et al., 2004; Nagueh, et al., 2004).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Makarenko, et al., 2004
Sheep and human left ventricles express both major titin isoforms in considerable amounts with N2BA:N2B ratios of ~0.35-0.43 and ~0.4-1.2, respectively.
“Sheep and human left ventricles express both major titin isoforms in considerable amounts with N2BA:N2B ratios of ~0.35–0.43 and ~0.4–1.2, respectively (Cazorla, et al., 2000; Kruger & Linke, 2006; Makarenko, et al., 2004; Nagueh, et al., 2004; Neagoe, et al., 2003).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Makarenko, et al., 2004
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References 42 · Cited by 332
- Authors
- Makarenko, I., Opitz, C. A., Leake, M. C., Neagoe, C., Kulke, M., Gwathmey, J. K., del Monte, F., Hajjar, R. J., & Linke, W. A.
- Affiliations
- Boston University (US)
- From the Physiology and Biophysics Laboratory (I.M., W.A.L.), University of Muenster, Muenster, Germany; Institute of Physiology (C.A.O., M.C.L., C.N., M.K., W.A.L.), University of Heidelberg, Heidelberg, Germany; Boston University Medical Center and Gwathmey, Inc. (J.K.G.), Boston, Mass; and the Cardiovascular Research Center (F.d.M., R.J.H.), Massachusetts General Hospital, Boston, Mass. The present address for I.M. is the Institute of Theoretical and Experimental Biophysics, Russian Academy of...
- Venue
- Circulation Research
- Published
- 2004-10
- Volume
- 95
- Issue
- 7
- Pages
- 708-716
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2100989502
- Cited by
- 332
- References
- 42
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 13 · 2023: 13 · 2022: 8 · 2021: 16 · 2020: 22 · 2019: 13 · 2018: 19 · 2017: 27 · 2016: 12 · 2015: 12 · 2014: 24 · 2013: 20 · 2012: 14
- FWCI
- 7.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- dilated cardiomyopathy, titin isoforms, passive stiffness, obscurin, myocardial fibrosis, diastolic function, heart failure, left ventricle
- MeSH terms
- Animals, Biomechanical Phenomena, Cardiomyopathy, Dilated, Fibrosis, Gene Expression Regulation, Heart Failure, Heart Ventricles, Humans, Models, Biological, Molecular Weight, Muscle Proteins, Myocardium, Myofibrils, Protein Kinases, RNA, Messenger, Blotting, Western, Protein Serine-Threonine Kinases, Pliability, Protein Isoforms, Reverse Transcriptase Polymerase Chain Reaction, Guanine Nucleotide Exchange Factors, Sus scrofa, Rho Guanine Nucleotide Exchange Factors, Connectin
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