Myofilament proteins: From cardiac disorders to proteomic changes

Yuan, Chao; Solaro, R. John

doi:10.1002/prca.200780076

Cited by 17 publications

(24 citation statements)

References 124 publications

(167 reference statements)

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“…Myofilament protein PTMs have emerged as a key mechanism regulating cardiac contractility, and increasing evidence has shown that the alteration of myofilament protein PTMs, particularly phosphorylation, can contribute to contractile dysfunction and heart failure [9–12, 25, 26, 29, 30]. Additionally, studies in humans, as well as large and small animals, have shown that aging and pathological cardiac conditions induce transmural changes in contractile function that correlate with differences in the modification status of myofilament proteins [1, 2, 5].…”

Section: Discussionmentioning

confidence: 99%

“…Contractile heterogeneity, in particular, has taken on increased significance with the demonstration that transmural changes in myocardial contractility not only occur in the failing heart [1–3], but may also be predictive of adverse cardiac events [7, 8]. Myocardial contractility is governed by a number of factors, including the size and duration of Ca 2+ transients, as well as the intrinsic properties of the contractile apparatus, which depend primarily on the expression of myofilament protein isoforms and post-translational modifications (PTMs) [9–12]. …”

Section: Introductionmentioning

confidence: 99%

“…Myofilament protein PTMs have emerged as a key mechanism regulating cardiac contractility in health and disease [9–12]. Previous studies in humans, as well as large and small animals, have shown that aging and pathological cardiac conditions induce contractile heterogeneity across the free wall of the left ventricle (LV) that correlates with differences in the modification status of myofilament proteins [1, 2, 5].…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive assessment of chamber-specific and transmural heterogeneity in myofilament protein phosphorylation by top-down mass spectrometry

Gregorich

Peng

Lane

et al. 2015

Journal of Molecular and Cellular Cardiology

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The heart is characterized by a remarkable degree of heterogeneity, the basis of which is a subject of active investigation. Myofilament protein post-translational modifications (PTMs) represent a critical mechanism regulating cardiac contractility, and emerging evidence shows that pathological cardiac conditions induce contractile heterogeneity that correlates with transmural variations in the modification status of myofilament proteins. Nevertheless, whether there exists basal heterogeneity in myofilament protein PTMs in the heart remains unclear. Here we have systematically assessed chamber-specific and transmural variations in myofilament protein PTMs, specifically, the phosphorylation of cardiac troponin I (cTnI), cardiac troponin T (cTnT), tropomyosin (Tpm), and myosin light chain 2 (MLC2). We show that the phosphorylation of cTnI and αTm vary in the different chambers of the heart, whereas the phosphorylation of MLC2 and cTnT does not. In contrast, no significant transmural differences were observed in the phosphorylation of any of the myofilament proteins analyzed. These results highlight the importance of appropriate tissue sampling—particularly for studies aimed at elucidating disease mechanisms and biomarker discovery—in order to minimize potential variations arising from basal heterogeneity in myofilament PTMs in the heart.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comprehensive assessment of chamber-specific and transmural heterogeneity in myofilament protein phosphorylation by top-down mass spectrometry

Gregorich

Peng

Lane

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…1 Aberrant protein PTMs together with mutations and alternatively spliced isoforms are increasingly recognized as important underlying mechanisms for cardiovascular diseases. 12–14 Hence, a comprehensive analysis of protein modifications is of high importance for understanding the disease mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Protein Modifications by Top-Down Mass Spectrometry

Zhang

2011

Circ Cardiovasc Genet

136

180

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Mass spectrometry (MS)-based proteomics is playing an increasingly important role in cardiovascular research. Proteomics includes not only identification and quantification of proteins, but also the characterization of protein modifications such as post-translational modifications and sequence variants. The conventional bottom-up approach, involving proteolytic digestion of proteins into small peptides prior to MS analysis, is routinely used for protein identification and quantification with high throughput and automation. Nevertheless, it has limitations in the analysis of protein modifications mainly due to the partial sequence coverage and loss of connections among modifications on disparate portions of a protein. An alternative approach, top-down MS, has emerged as a powerful tool for the analysis of protein modifications. The top-down approach analyzes whole proteins directly, providing a “bird’s eye” view of all existing modifications. Subsequently, each modified protein form can be isolated and fragmented in the mass spectrometer to locate the modification site. The incorporation of the non-ergodic dissociation methods such as electron capture dissociation (ECD) greatly enhances the top-down capabilities. ECD is especially useful for mapping labile post-translational modifications which are well-preserved during the ECD fragmentation process. Top-down MS with ECD has been successfully applied to cardiovascular research with the unique advantages in unraveling the molecular complexity, quantifying modified protein forms, complete mapping of modifications with full sequence coverage, discovering unexpected modifications, and identifying and quantifying positional isomers and determining the order of multiple modifications. Nevertheless, top-down MS still needs to overcome some technical challenges to realize its full potential. Herein, we reviewed the advantages and challenges of top-down methodology with a focus on its application in cardiovascular research.

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“…Prior to this, most studies of post-translational modifications (PTMs) of cardiac myofilaments addressed more common PTM types such as phosphorylation, glycosylation and proteolysis. 14-17 …”

mentioning

confidence: 99%

Nitroxyl, Redox Switches, Cardiac Myofilaments, and Heart Failure

Moss

2012

Circulation Research

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Myofilament proteins: From cardiac disorders to proteomic changes

Cited by 17 publications

References 124 publications

Comprehensive assessment of chamber-specific and transmural heterogeneity in myofilament protein phosphorylation by top-down mass spectrometry

Comprehensive assessment of chamber-specific and transmural heterogeneity in myofilament protein phosphorylation by top-down mass spectrometry

Comprehensive Analysis of Protein Modifications by Top-Down Mass Spectrometry

Nitroxyl, Redox Switches, Cardiac Myofilaments, and Heart Failure

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