Multiomics approach to identify novel biomarkers for dilated cardiomyopathy: Proteome and transcriptome analyses of 4C30 dilated cardiomyopathy mouse model

Nishigori, Mitsuhiro; Yanagimoto, Hiroaki; Mochiduki, Akikazu; Minamino, Naoto

doi:10.1002/bip.22809

Cited by 4 publications

(5 citation statements)

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“…In total, 9,067 protein clusters were observed, with approximately 4,500 proteins reproducibly identified for each species (Fig 1B, S5 Fig and S5 Table). This depth is in line with other previous studies of cardiac proteomes [39–41].…”

Section: Resultssupporting

confidence: 93%

Conservation and divergence of protein pathways in the vertebrate heart

et al. 2019

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Heart disease is the leading cause of death in the western world. Attaining a mechanistic understanding of human heart development and homeostasis and the molecular basis of associated disease states relies on the use of animal models. Here, we present the cardiac proteomes of 4 model vertebrates with dual circulatory systems: the pig (Sus scrofa), the mouse (Mus musculus), and 2 frogs (Xenopus laevis and Xenopus tropicalis). Determination of which proteins and protein pathways are conserved and which have diverged within these species will aid in our ability to choose the appropriate models for determining protein function and to model human disease. We uncover mammalian- and amphibian-specific, as well as species-specific, enriched proteins and protein pathways. Among these, we find and validate an enrichment in cell-cycle–associated proteins within Xenopus laevis. To further investigate functional units within cardiac proteomes, we develop a computational approach to profile the abundance of protein complexes across species. Finally, we demonstrate the utility of these data sets for predicting appropriate model systems for studying given cardiac conditions by testing the role of Kielin/chordin-like protein (Kcp), a protein found as enriched in frog hearts compared to mammals. We establish that germ-line mutations in Kcp in Xenopus lead to valve defects and, ultimately, cardiac failure and death. Thus, integrating these findings with data on proteins responsible for cardiac disease should lead to the development of refined, species-specific models for protein function and disease states.

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Section: Resultssupporting

confidence: 93%

Conservation and divergence of protein pathways in the vertebrate heart

et al. 2019

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“…Firstly, to identify differentially expressed proteins between Group D and Group N, we performed non-target proteome analysis using nano-liquid chromatography, coupled with tandem mass spectrometry (LC-MS/MS), followed by quantitative data analysis using the 2DICAL software 20,21 . 2DICAL data analysis resulted in the identification and quantification of 15,240 peptide peaks from all the aortic media samples analysed in this study.…”

Section: Resultsmentioning

confidence: 99%

“…were performed according to our previous report 21 . Aortic media tissues were pulverized under frozen conditions at −80 °C using a Shake Master Neo instrument (BMS, Tokyo, Japan), suspended in methanol, and aliquoted to obtain a target amount of tissue (2 mg) in each tube.…”

Section: Lc-ms/ms Analysis and Protein Identification And Quantificatmentioning

confidence: 99%

“…After centrifugation and evaporation to dryness, the pulverized tissue was suspended in 2% sodium deoxycholate and heated at 95 °C for 10 min to denature proteins and inactivate intrinsic proteases. After cooling, urea (final concentration: 2 M) and ammonium bicarbonate (final concentration: 50 mM) were added and denatured tissues were digested with lysyl endopeptidase (1 μg; WAKO Pure Chemicals, Osaka, Japan) at 37 °C for 3 h, followed by trypsin (3.3 μg; sequence grade; Promega, Madison, WI, USA) at 37 °C for 20 h. Sodium deoxycholate was removed using the phase-transfer method 46 , and the resulting digests were desalted using C18 StageTips 21,47 . Tryptic peptides were dissolved in 50 μL of 0.1% formic acid and their concentrations were determined using a Qubit fluorometer (Life Technologies, Carlsbad, CA, USA).…”

Section: Lc-ms/ms Analysis and Protein Identification And Quantificatmentioning

confidence: 99%

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Discovery of novel biomarkers for atherosclerotic aortic aneurysm through proteomics-based assessment of disease progression

Yanagimoto

Nishigori

Murakami

et al. 2020

Sci Rep

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Since aortic aneurysms (AAs) are mostly asymptomatic, but they have a high mortality rate upon rupture, their detection and progression evaluation are clinically important issues. To discover diagnostic biomarkers for AA, we performed proteome analysis of aortic media from patients with thoracic atherosclerotic AA (TAAA), comparing protein levels between the aneurysm and normal tissue areas. After hierarchical clustering analysis of the proteome analysis data, tissue samples were classified into three groups, regardless of morphological features. This classification was shown to reflect disease progression stage identified by pathological examination. This proteomics-based staging system enabled us to identify more significantly altered proteins than the morphological classification system. In subsequent data analysis, Niemann-Pick disease type C2 protein (NPC2) and insulin-like growth factor-binding protein 7 (IGFBP7) were selected as novel biomarker candidates for AA and were compared with the previously reported biomarker, thrombospondin 1 (THBS1). Blood concentrations of NPC2 and IGFBP7 were significantly increased, while THBS1 levels were decreased in TAAA and abdominal atherosclerotic AA patients. Receiver operating characteristic analysis of AA patients and healthy controls showed that NPC2 and IGFBP7 have higher specificity and sensitivity than THBS1. Thus, NPC2 and IGFBP7 are promising biomarkers for the detection and progression evaluation of AA. Aortic aneurysm (AA) is a disease of aortic dilation that results in a bulge or swelling in the aorta. AAs are mostly asymptomatic, but they have a high mortality rate upon dissociation or rupture 1-3. The early detection and progression evaluation of AA are clinically urgent issues, because surgical treatments, such as the implantation of stent grafts or aortic prosthesis, are available 4,5. AA is often detected by chance in diagnostic imaging, for example, by computed tomography, magnetic resonance imaging, or ultrasonic echo for other diseases, or during voluntary health examination 6. However, highly sensitive and specific diagnostic tests for the detection of AA have not yet been developed. D-dimer and C-reactive protein (CRP) levels in the blood have been reported to be suitable for the diagnosis of AA 7-9. However, these markers have poor disease specificity and effectiveness due to their primary design and aims, and do not reflect aortic tissue degeneration during the formation and progression of the aneurysm 10,11. Therefore, novel biomarkers based on the molecular mechanism of the development and progression of AA are highly desired for the diagnosis of AA. A major cause of aortic aneurysm is atherosclerosis. In the advanced atherosclerosis lesion, aortic wall structure is usually disrupted and embrittled. Fragile aortas are then enlarged, resulting in an aneurysm 12. Although the pathogenic mechanism of atherosclerosis is not fully understood, it is well recognized that endothelial cell dysfunction occurs as a first step, followed by the accumulation...

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“…Samples for mass spectrometric (MS) analysis were prepared according to our previous reports, with some modifications [ 15 , 20 ]. The three SFUC fractions (200 μg protein for each fraction) of TAA1, TAA2, TAA3, and HC samples were individually mixed with sodium deoxycholate (final concentration: 0.5%) and heated at 95 °C for 10 min to denature proteins and inactivate intrinsic proteases.…”

Section: Methodsmentioning

confidence: 99%

Serum proteomic identification and validation of two novel atherosclerotic aortic aneurysm biomarkers, profilin 1 and complement factor D

Murakami,

Nishigori,

Yagi

et al. 2023

Proteome Sci

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Background Effective diagnostic biomarkers for aortic aneurysm (AA) that are detectable in blood tests are required because early detection and rupture risk assessment of AA can provide insights into medical therapy and preventive treatments. However, known biomarkers for AA lack specificity and reliability for clinical diagnosis. Methods We performed proteome analysis of serum samples from patients with atherosclerotic thoracic AA (TAA) and healthy control (HC) subjects to identify diagnostic biomarkers for AA. Serum samples were separated into low-density lipoprotein, high-density lipoprotein, and protein fractions, and the major proteins were depleted. From the proteins identified in the three fractions, we narrowed down biomarker candidates to proteins uniformly altered in all fractions between patients with TAA and HC subjects and evaluated their capability to discriminate patients with TAA and those with abdominal AA (AAA) from HC subjects using receiver operating characteristic (ROC) analysis. For the clinical validation, serum concentrations of biomarker candidates were measured in patients with TAA and AAA registered in the biobank of the same institute, and their capability for the diagnosis was evaluated. Results Profilin 1 (PFN1) and complement factor D (CFD) showed the most contrasting profiles in all three fractions between patients with TAA and HC subjects and were selected as biomarker candidates. The PFN1 concentration decreased, whereas the CFD concentration increased in the sera of patients with TAA and AAA when compared with those of HC subjects. The ROC analysis showed that these proteins could discriminate patients with TAA and AAA from HC subjects. In the validation study, these candidates showed significant concentration differences between patients with TAA or AAA and controls. PFN1 and CFD showed sufficient area under the curve (AUC) in the ROC analysis, and their combination further increased the AUC. The serum concentrations of PFN1 and CFD also showed significant differences between patients with aortic dissection and controls in the validation study. Conclusion PFN1 and CFD are potential diagnostic biomarkers for TAA and AAA and measurable in blood samples; their diagnostic performance can be augmented by their combination. These biomarkers may facilitate the development of diagnostic systems to identify patients with AA.

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Multiomics approach to identify novel biomarkers for dilated cardiomyopathy: Proteome and transcriptome analyses of 4C30 dilated cardiomyopathy mouse model

Cited by 4 publications

References 35 publications

Conservation and divergence of protein pathways in the vertebrate heart

Conservation and divergence of protein pathways in the vertebrate heart

Discovery of novel biomarkers for atherosclerotic aortic aneurysm through proteomics-based assessment of disease progression

Serum proteomic identification and validation of two novel atherosclerotic aortic aneurysm biomarkers, profilin 1 and complement factor D

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