Top-Down Quantitative Proteomics Identified Phosphorylation of Cardiac Troponin I as a Candidate Biomarker for Chronic Heart Failure
Open accessAbstract
The rapid increase in the prevalence of chronic heart failure (CHF) worldwide underscores an urgent need to identify biomarkers for the early detection of CHF. Post-translational modifications (PTMs) are associated with many critical signaling events during disease progression and thus offer a plethora of candidate biomarkers. We have employed a top-down quantitative proteomics methodology for comprehensive assessment of PTMs in whole proteins extracted from normal and diseased tissues. We systematically analyzed 36 clinical human heart tissue samples and identified phosphorylation of cardiac troponin I (cTnI) as a candidate biomarker for CHF. The relative percentages of the total phosphorylated cTnI forms over the entire cTnI populations (%P(total)) were 56.4 ± 3.5%, 36.9 ± 1.6%, 6.1 ± 2.4%, and 1.0 ± 0.6% for postmortem hearts with normal cardiac function (n = 7), early stage of mild hypertrophy (n = 5), severe hypertrophy/dilation (n = 4), and end-stage CHF (n = 6), respectively. In fresh transplant samples, the %P(total) of cTnI from nonfailing donor (n = 4), and end-stage failing hearts (n = 10) were 49.5 ± 5.9% and 18.8 ± 2.9%, respectively. Top-down MS with electron capture dissociation unequivocally localized the altered phosphorylation sites to Ser22/23 and determined the order of phosphorylation/dephosphorylation. This study represents the first clinical application of top-down MS-based quantitative proteomics for biomarker discovery from tissues, highlighting the potential of PTMs as disease biomarkers.
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In heart disease, proteoform dynamics have been observed on proteins such as cardiac troponin I, apolipoprotein C-III, and B-type natriuretic peptide, the latter a key regulator of blood pressure and also the gold standard biomarker for clinically assessing heart failure.
“In heart disease, proteoform dynamics have been observed on proteins such as cardiac troponin I 64 , apolipoprotein C-III 65 , and B-type natriuretic peptide, the latter a key regulator of blood pressure and also the gold standard biomarker for clinically assessing heart failure 66 .”
From How many human proteoforms are there? (2018) · cites this paper as [64]
Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredTiambeng and Roberts led development of a nanoproteomics strategy using functionalized magnetic nanoparticles with a peptide affinity ligand to specifically target cardiac troponin I.
“To address the limitation of the antibody-based approach, Tiambeng and Roberts led the development of a nanoproteomics strategy using functionalized magnetic NPs with a peptide affinity ligand to specifically target cardiac troponin I (cTnI) [65–67], an important and gold-standard cardiac biomarker [68].”
From Top-down proteomics: challenges, innovations, and applications in basic and clinical research (2020) · cites this paper as [65]
Decreased cTnI phosphorylation was found in hearts with increased chronic heart failure.
“Additionally, decreased level of cTnI phosphorylation was found in hearts with increased chronic heart failure [61]”
From Top-down proteomics: challenges, innovations, and applications in basic and clinical research (2020) · cites this paper as [61]
In the heart, protein isoform switching and PTMs regulate cardiac contraction and relaxation and contribute to heart failure progression.
“For example, in the heart, protein isoform switching [141], and PTMs are known to regulate cardiac contraction and relaxation, as well as play a role in the progression of heart failure [61,142,143].”
From Top-down proteomics: challenges, innovations, and applications in basic and clinical research (2020) · cites this paper as [61]
The PTM profiles of cTnI can function as molecular fingerprints of cellular signaling pathway activity with the potential to serve as next-generation biomarkers.
“The PTM profiles of cTnI can function as molecular fingerprints of cellular signaling pathway activity with the potential to serve as the next-generation biomarkers27,32,33.”
From Nanoproteomics enables proteoform-resolved analysis of low-abundance proteins in human serum (2020) · cites this paper as [32]
C-terminal truncated cTnI proteoforms were identified and characterized in the postmortem samples.
“We also identified and characterized C-terminal truncated cTnI proteoforms found in the postmortem samples (Fig. 2h), which is consistent with our previous report32.”
From Nanoproteomics enables proteoform-resolved analysis of low-abundance proteins in human serum (2020) · cites this paper as [32]
ppcTnI was the predominant cTnI proteoform in the non-diseased donor heart, whereas non-phosphorylated cTnI was the most abundant cTnI proteoform in the dilated cardiomyopathy heart.
“We found ppcTnI to be the predominant cTnI proteoform in the non-diseased donor heart (Fig. 2f), whereas non-phosphorylated cTnI was found to be the most abundant cTnI proteoform in the dilated cardiomyopathy heart (Fig. 2g), consistent with previous reports suggesting phosphorylation of cTnI as a potential biomarker for heart diseases27,31,32.”
From Nanoproteomics enables proteoform-resolved analysis of low-abundance proteins in human serum (2020) · cites this paper as [32]
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Toby, T. K., Fornelli, L., Srzentić, K., DeHart, C. J., Levitsky, J., Friedewald, J., & Kelleher, N. L. (2019) · Nature Protocols · doi:10.1038/s41596-018-0085-7 · Cited by 86 · see citing works
New Mass-Spectrometry-Compatible Degradable Surfactant for Tissue Proteomics
Chang, Y.-H., Gregorich, Z. R., Chen, A. J., Hwang, L., Guner, H., Yu, D., Zhang, J., & Ge, Y. (2015) · Journal of Proteome Research · doi:10.1021/pr5012679 · Cited by 80 · see citing works
Self-citationNanoproteomics enables proteoform-resolved analysis of low-abundance proteins in human serum
Tiambeng, T. N., Roberts, D. S., Brown, K. A., Zhu, Y., Chen, B., Wu, Z., Mitchell, S. D., Guardado-Alvarez, T. M., Jin, S., & Ge, Y. (2020) · Nature Communications · doi:10.1038/s41467-020-17643-1 · Cited by 76 · see citing works
Self-citationGuner, H., Close, P. L., Cai, W., Zhang, H., Peng, Y., Gregorich, Z. R., & Ge, Y. (2014) · Journal of the American Society for Mass Spectrometry · doi:10.1007/s13361-013-0789-4 · Cited by 73 · see citing works
Self-citationProteomics in heart failure: top-down or bottom-up?
Gregorich, Z. R., Chang, Y.-H., & Ge, Y. (2014) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-014-1471-9 · Cited by 69 · see citing works
Self-citationSpecific Enrichment of Phosphoproteins Using Functionalized Multivalent Nanoparticles
Hwang, L., Ayaz-Guner, S., Gregorich, Z. R., Cai, W., Valeja, S. G., Jin, S., & Ge, Y. (2015) · Journal of the American Chemical Society · doi:10.1021/ja511833y · Cited by 70 · see citing works
Self-citationWijnker, P. J. M., Foster, D. B., Tsao, A. L., Frazier, A. H., dos Remedios, C. G., Murphy, A. M., Stienen, G. J. M., & van der Velden, J. (2013) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00498.2012 · Cited by 50 · see citing works
Tucholski, T., Knott, S. J., Chen, B., Pistono, P., Lin, Z., & Ge, Y. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.8b04082 · Cited by 49 · see citing works
Self-citationWei, L., Gregorich, Z. R., Lin, Z., Cai, W., Jin, Y., McKiernan, S. H., McIlwain, S., Aiken, J. M., Moss, R. L., Diffee, G. M., et al. (2018) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra117.000124 · Cited by 47 · see citing works
Self-citationFert-Bober, J., Murray, C. I., Parker, S. J., & Van Eyk, J. E. (2018) · Circulation Research · doi:10.1161/circresaha.118.310966 · Cited by 45 · see citing works
In-depth proteomic analysis of human tropomyosin by top-down mass spectrometry
Peng, Y., Yu, D., Gregorich, Z., Chen, X., Beyer, A. M., Gutterman, D. D., & Ge, Y. (2013) · Journal of Muscle Research and Cell Motility · doi:10.1007/s10974-013-9352-y · Cited by 42 · see citing works
Self-citationChen, B., Hwang, L., Ochowicz, W., Lin, Z., Guardado-Alvarez, T. M., Cai, W., Xiu, L., Dani, K., Colah, C., Jin, S., et al. (2017) · Chemical Science · doi:10.1039/c6sc05435h · Cited by 43 · see citing works
Self-citationThe continuing evolution of cardiac troponin I biomarker analysis: from protein to proteoform
Soetkamp, D., Raedschelders, K., Mastali, M., Sobhani, K., Bairey Merz, C. N., & Van Eyk, J. (2017) · Expert Review of Proteomics · doi:10.1080/14789450.2017.1387054 · Cited by 36 · see citing works
Effective Top-Down LC/MS+ Method for Assessing Actin Isoforms as a Potential Cardiac Disease Marker
Chen, Y.-C., Ayaz-Guner, S., Peng, Y., Lane, N. M., Locher, M. R., Kohmoto, T., Larsson, L., Moss, R. L., & Ge, Y. (2015) · Analytical Chemistry · doi:10.1021/acs.analchem.5b01745 · Cited by 31 · see citing works
Self-citationSchmitt, N. D., & Agar, J. N. (2017) · Journal of Mass Spectrometry · doi:10.1002/jms.3953 · Cited by 29 · see citing works
Intact-Mass Analysis Facilitating the Identification of Large Human Heart Proteoforms
Schaffer, L. V., Tucholski, T., Shortreed, M. R., Ge, Y., & Smith, L. M. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b02343 · Cited by 17 · see citing works
Self-citation
- Authors
- Zhang, J., Guy, M. J., Norman, H. S., Chen, Y.-C., Xu, Q., Dong, X., Guner, H., Wang, S., Kohmoto, T., Young, K. H., Moss, R. L., & Ge, Y.
- Affiliations
- University of Wisconsin–Madison (US)
- Human Proteomics Program, ∥Department of Physiology, ⊥Department of Biostatistics and Medical Informatics, #Department of Surgery, ¶Department of Pathology and Laboratory Medicine, School of Medicine and Public Health and ‡School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53706, United States
- Corresponding author
- Ge, Ying
- ORCID
- Venue
- Journal of Proteome Research
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-07-28
- Volume
- 10
- Issue
- 9
- Pages
- 4054-4065
- ISSN
- 1535-3893 (ISSN-L)
- 1535-3907
- PMC
- PMC3170873
- OpenAlex
- W2061635752
- Cited by
- 194
- References
- 66
- Citations by year
- 2026: 12 · 2025: 2 · 2024: 8 · 2023: 12 · 2022: 10 · 2021: 11 · 2020: 14 · 2019: 10 · 2018: 21 · 2017: 9 · 2016: 16 · 2015: 19 · 2014: 25 · 2013: 13 · 2012: 9
- FWCI
- 7.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Proteome Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- University of Wisconsin-Madison
- National Heart, Lung, and Blood Institute (R37HL082900, R37 HL82900, R01HL096971)
- Topics
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- chronic heart failure, cardiac troponin I, phosphorylation, post-translational modification, biomarker discovery, electron capture dissociation, cardiac hypertrophy, heart transplantation, dephosphorylation, myocardium
- MeSH terms
- Amino Acid Sequence, Chronic Disease, Heart Failure, Humans, Molecular Sequence Data, Myocardium, Phenotype, Phosphorylation, Protein Processing, Post-Translational, Mass Spectrometry, Biomarkers, Linear Models, Troponin I, Proteomics
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