Plasma proteomic analysis of stable coronary artery disease indicates impairment of reverse cholesterol pathway

Tanwar, Vinay Singh; Bhardwaj, Gourav; Bhardwaj, Nitin; Ahmad, Shadab; Garg, Gaurav; Sreenivas,; Karthikeyan, Ganesan; Seth, Sandeep; Sengupta, Shantanu

doi:10.1038/srep28042

Cited by 24 publications

(18 citation statements)

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“…The data obtained highlight peculiar characteristics of patients having higher residual cardiovascular risk due to higher levels of Apo C‐III. In particular, our findings demonstrated that there is a strong relationship among Apos which are under expressed in patients with low level of Apo C‐III, thus confirming the involvement of cholesterol efflux as already demonstrated by Basak et al …”

Section: Discussionsupporting

confidence: 90%

“…The plasma proteome of CAD patients has been widely studied: the expression of plasma proteins of CAD patients was studied against healthy non‐CAD controls and patients with acute coronary syndrome were compared to stable patients . Several studies also demonstrated that urinary peptide biomarkers reflect atherosclerosis in mice and humans .…”

Section: Introductionmentioning

confidence: 99%

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Plasma Proteome Profiles of Stable CAD Patients Stratified According to Total Apo C‐III Levels

Manfredi

Chiariello

Conte

et al. 2018

Proteomics Clinical Apps

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Plasma Proteome Profiles of Stable CAD Patients Stratified According to Total Apo C‐III Levels

Manfredi

Chiariello

Conte

et al. 2018

Proteomics Clinical Apps

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“…Multiple protein changes have been also reported to date in plasma. These studies, involving use of both gel-based and non-gel-based techniques (reviewed in [ 20 ]), addressed the identification of features associated with specific CVD phenotypes, including abdominal aneurism progression [ 21 ]; fibrin clot-bound proteins in acute myocardial infarction [ 22 ]; stable coronary artery disease pathophysiology [ 23 ]; prognostic biomarkers in peripheral arterial occlusive disease [ 24 ]; venous thromboembolism risk prediction [ 25 ]; and extracellular matrix remodeling in hypertrophic cardiomyopathy [ 26 ]. Significant changes in multiple proteins included various forms of apoliproteins [ 23 ]; thrombospondin 1 [ 10 ]; alpha 2 macroglobulin [ 10 ]; transthyretin [ 24 ]; complement factor B [ 24 ]; platelet-derived growth factor β [ 25 ]; and fibronectin [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Plasma proteomic analysis reveals altered protein abundances in cardiovascular disease

et al. 2018

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BackgroundCardiovascular disease (CVD) describes the pathological conditions of the heart and blood vessels. Despite the large number of studies on CVD and its etiology, its key modulators remain largely unknown. To this end, we performed a comprehensive proteomic analysis of blood plasma, with the scope to identify disease-associated changes after placing them in the context of existing knowledge, and generate a well characterized dataset for further use in CVD multi-omics integrative analysis.MethodsLC–MS/MS was employed to analyze plasma from 32 subjects (19 cases of various CVD phenotypes and 13 controls) in two steps: discovery (13 cases and 8 controls) and test (6 cases and 5 controls) set analysis. Following label-free quantification, the detected proteins were correlated to existing plasma proteomics datasets (plasma proteome database; PPD) and functionally annotated (Cytoscape, Ingenuity Pathway Analysis). Differential expression was defined based on identification confidence (≥ 2 peptides per protein), statistical significance (Mann–Whitney p value ≤ 0.05) and a minimum of twofold change.ResultsPeptides detected in at least 50% of samples per group were considered, resulting in a total of 3796 identified proteins (838 proteins based on ≥ 2 peptides). Pathway annotation confirmed the functional relevance of the findings (representation of complement cascade, fibrin clot formation, platelet degranulation, etc.). Correlation of the relative abundance of the proteins identified in the discovery set with their reported concentrations in the PPD was significant, confirming the validity of the quantification method. The discovery set analysis revealed 100 differentially expressed proteins between cases and controls, 39 of which were verified (≥ twofold change) in the test set. These included proteins already studied in the context of CVD (such as apolipoprotein B, alpha-2-macroglobulin), as well as novel findings (such as low density lipoprotein receptor related protein 2 [LRP2], protein SZT2) for which a mechanism of action is suggested.ConclusionsThis proteomic study provides a comprehensive dataset to be used for integrative and functional studies in the field. The observed protein changes reflect known CVD-related processes (e.g. lipid uptake, inflammation) but also novel hypotheses for further investigation including a potential pleiotropic role of LPR2 but also links of SZT2 to CVD.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1476-9) contains supplementary material, which is available to authorized users.

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“…its prolonged treatment lowers the levels of pyruvate and inhibits glucose induced ATP production in pancreatic cells 53 55 . Also, in a case control study in the Indian population, we have previously shown that high levels of cysteine is associated with cardiovascular disease 32 , and interestingly total proteins in CAD patients was shown to be significantly lower as compared to control groups 56 . Interestingly, high leucine diet has been proposed to be helpful in attenuating heart diseases 57 .…”

Section: Cysteine and Pyruvate Relationmentioning

confidence: 93%

Ncl1 mediated metabolic rewiring critical during metabolic stress

Bhat

Chakraborty

Adlakha

et al. 2019

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Nutritional limitation has been vastly studied, however, there is limited knowledge of how cells maintain homeostasis in excess nutrients. In this study, using yeast as a model system, we show that some amino acids are toxic at higher concentrations. With cysteine as a physiologically relevant example, we delineated the pathways/processes that are altered and those that are involved in survival in presence of elevated levels of this amino acid. Using proteomics and metabolomics approach, we found that cysteine upregulates proteins involved in amino acid metabolism, alters amino acid levels, and inhibits protein translation, events that are rescued by leucine supplementation. Through a comprehensive genetic screen we show that leucine mediated effect depends on a tRNA methyltransferase (Ncl1), absence of which decouples cell"s transcription and translation, inhibits the conversation of leucine to ketoisocaproate and leads to TCA cycle block. We therefore, propose a role of Ncl1 in regulating metabolic homeostasis through translational control.In this study, using Saccharomyces cerevisiae as a model, we used a combination of genetic, proteomic, transcriptomic and metabolic approach to understand cysteine induced systemic alteration. We show that cysteine inhibits protein translation and alters the amino acid metabolism, effects which are reversed by supplementation of leucine. We also show that a tRNA methyltransferase (NCL1) is involved in survival during cysteine stress, absence of which inhibited the conversation of leucine to ketoisocaproate (KIC), a necessary step for mitigating the effect of cysteine. Thus, this study not only uncovered the cellular insights during high levels cysteine, but also highlighted the novel role of NCL1 in regulating the metabolism during excess cysteine. Results Metabolic alterations due to excess amino acids induce growth defectGrowth screening of S cerevisiae (BY4741) in the presence of high concentrations of amino acids revealed that a few amino acids -cysteine, isoleucine, valine, tryptophan and phenylalanine inhibited growth (Fig. 1A). To test if the imbalance due to excess of an amino acid resulting in the growth inhibition could be abrogated in the presence of other amino acids, we did a comprehensive amino acid supplementation screening. We found that the amino acid, leucine could completely rescue the growth inhibition due to isoleucine, valine, tryptophan and phenylalanine but not cysteine, where the rescue was partial ( Fig 1B). The effect of leucine could be because the yeast strain used in this study, BY4741, is auxotrophic for leucine. To confirm this, we performed the same experiment using a prototrophic wild type strain, S288C, and found that except cysteine, none of the other amino acids inhibited growth ( Fig 1C). Further, the growth inhibitory effect of cysteine was lower compared to BY4741. This suggests that intracellular concentration of leucine might play a role in alleviating amino-acid mediated toxicity. This was further confirmed by deleting the gene invol...

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Plasma proteomic analysis of stable coronary artery disease indicates impairment of reverse cholesterol pathway

Cited by 24 publications

References 50 publications

Plasma Proteome Profiles of Stable CAD Patients Stratified According to Total Apo C‐III Levels

Plasma Proteome Profiles of Stable CAD Patients Stratified According to Total Apo C‐III Levels

Plasma proteomic analysis reveals altered protein abundances in cardiovascular disease

Ncl1 mediated metabolic rewiring critical during metabolic stress

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