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Exploring the human plasma proteome for humoral mediators of remote ischemic preconditioning--a word of caution
Erik Helgeland1, Lars Ertesvåg Breivik1, Marc Vaudel1
1Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
Insights
Remote ischemic preconditioning (RIPC) aims to protect the heart, but identifying its protein mediators in human plasma proved challenging. This study found no reproducible proteomic regulations, suggesting further research into small humoral factors for RIPC cardioprotection.
Area of Science:
- Cardiovascular Research
- Proteomics
- Translational Medicine
Background:
- Cardiovascular diseases remain a leading cause of death globally, with myocardial infarctions being a major contributor.
- Ischemia-reperfusion injury following revascularization is a significant clinical challenge, despite advances in treatment.
- Remote ischemic preconditioning (RIPC) offers a non-invasive strategy to enhance cardiac tolerance to ischemia, but its underlying mechanisms require elucidation.
Purpose of the Study:
- To investigate and validate potential protein biomarkers mediating cardioprotection induced by RIPC in human plasma.
- To address the heterogeneity in reported RIPC-induced proteomic changes and provide reproducible experimental data.
- To identify novel targets for enhancing ischemic tolerance through RIPC.
Main Methods:
- Unbiased, in-depth analysis of the human plasma proteome before and after RIPC using untargeted proteomics.
- Monitoring of 23 previously reported protein markers associated with RIPC.
- Accurate quantification of 394 plasma proteins.
Main Results:
- Only 28 of 68 reported protein markers could be mapped to reviewed protein sequences.
- No significant regulation of the monitored protein markers could be reproducibly estimated.
- No significant regulation was confidently and reproducibly assessed among the 394 quantified plasma proteins.
Conclusions:
- Reproducible identification and validation of RIPC-induced plasma proteomic regulations are difficult with current methods.
- The study suggests that further research should focus on small humoral factors rather than large proteins as RIPC mediators.
- The comprehensive proteomic dataset is made publicly available to facilitate future research into RIPC mechanisms and targets.
Abstract:
Despite major advances in early revascularization techniques, cardiovascular diseases are still the leading cause of death worldwide, and myocardial infarctions contribute heavily to this. Over the past decades, it has become apparent that reperfusion of blood to a previously ischemic area of the heart causes damage in and of itself, and that this ischemia reperfusion induced injury can be reduced by up to 50% by mechanical manipulation of the blood flow to the heart. The recent discovery of remote ischemic preconditioning (RIPC) provides a non-invasive approach of inducing this cardioprotection at a distance. Finding its endogenous mediators and their operative mode is an important step toward increasing the ischemic tolerance. The release of humoral factor(s) upon RIPC was recently demonstrated and several candidate proteins were published as possible mediators of the cardioprotection. Before clinical applicability, these potential biomarkers and their efficiency must be validated, a task made challenging by the large heterogeneity in reported data and results. Here, in an attempt to reproduce and provide more experimental data on these mediators, we conducted an unbiased in-depth analysis of the human plasma proteome before and after RIPC. From the 68 protein markers reported in the literature, only 28 could be mapped to manually reviewed (Swiss-Prot) protein sequences. 23 of them were monitored in our untargeted experiment. However, their significant regulation could not be reproducibly estimated. In fact, among the 394 plasma proteins we accurately quantified, no significant regulation could be confidently and reproducibly assessed. This indicates that it is difficult to both monitor and reproduce published data from experiments exploring for RIPC induced plasma proteomic regulations, and suggests that further work should be directed towards small humoral factors. To simplify this task, we made our proteomic dataset available via ProteomeXchange, where scientists can mine for novel potential targets.
