Heart Attack: Working together

Heart attacks have a ripple effect on how other organs exchange biomolecules that help the heart respond to injury.
  1. Regan Odongo
  2. Tunahan Çakır  Is a corresponding author
  1. Gebze Technical University, Turkey

A healthy heart relies on a close network of organs to work properly. Indeed, its cells require high levels of energy which is provided by biomolecules transported in the blood from other organs. If the blood supply is blocked, this can result in a heart attack which damages the heart’s muscle cells leading to the organ beating irregularly or, in some cases, failing all together. Our current understanding of heart attacks is limited to examining the alterations to tissues in the heart, but less is known about what happens in other organs.

Recent advances in molecular methods have begun to shed light on this issue, showing, for instance, that gene expression in the spleen and liver of pigs is significantly modified following a heart attack (Zimmermann et al., 2017). Computer simulations can predict the molecular alterations taking place during complex diseases, and could be harnessed to examine how different tissues respond to a heart attack (Priest and Tontonoz, 2019). Now, in eLife, Adil Mardinoglu (Royal Institute of Technology), Jan Boren (Sahlgrenska University Hospital) and colleagues – including Muhammad Arif and Martina Klevstig as joint first authors – report how they used this method, and other techniques, to investigate how heart attacks alter fat, skeletal muscle and liver tissues (Arif et al., 2021).

To identify which genes are altered in these tissues, the team (who are based in Sweden, Turkey and the United Kingdom) triggered acute heart attacks in mice by surgically blocking some of the arteries that supply blood to muscle cells in the heart (Figure 1). They then collected samples from the mice’s heart, skeletal muscle, fat tissue and liver, and measured how every single protein-coding gene was expressed using a highly sensitive technique called RNA sequencing. Comparing results from the heart attack model to tissue samples from control mice revealed striking changes in a number of genes, including four that had not previously been associated with this disease (Flnc, Lgals3, Prkaca and Pprc1). Most of these molecular changes took place after 24 hours, with the most profound effects occurring in the heart’s tissues.

Heart attacks cause molecular changes in multiple tissues.

Acute heart attacks were induced in mice by blocking some of the arteries that supply blood to the heart, resulting in an irregular heartbeat. Samples were then collected from the heart, skeletal muscle, liver and adipose, or 'fat', tissues of these mice (red heart) and control animals that had not undergone a heart attack (green heart). RNA sequencing revealed that the heart attack altered genes expressed in all four of these tissues. Further computational simulations suggest that these genetic changes alter the production of metabolites that are then taken up by the other tissues (represented by arrows).

Image credit: Regan Odongo.

Further analysis showed that genes associated with the immune system, RNA processes and mitochondrial function were commonly altered in the heart, skeletal muscle and fat tissues. Arif et al. also found groups of genes that were only modified in specific tissues. These unique clusters had a variety of roles, ranging from reacting to the heart attack to breaking down metabolites (biomolecules derived from glucose) so muscle cells in the heart can adequately respond to the injury. These findings suggest that the molecular changes induced by a heart attack have a ripple effect that changes how genes are expressed in other organs.

Next, Arif et al. performed computational simulations to predict which of the metabolites produced by these tissues might have an important role in supplying energy to the heart. To do this, they used a technique called reporter metabolite analysis which identifies key metabolites based on the genes expressed (Patil and Nielsen, 2005). Some of the metabolites were detected in all four tissues, while others were only found in either the heart, skeletal muscle, fat or liver. These metabolites were consistent with physiological changes commonly observed in patients that have experienced a heart attack (Doenst et al., 2013).

Advanced computational simulations were then conducted on a model in which all four tissues are linked together by blood vessels. This predicted that some of the metabolites synthesised by the liver are released into the blood and taken up by the heart’s tissues (Figure 1). The model also showed that some of the metabolites frequently found in the blood samples of heart attack patients are released from fat tissues and taken up by the liver and skeletal muscles. Taken together, these findings suggest that the heart, skeletal muscles, fat and liver all have a distinct molecular response to a heart attack. However, these genetic changes allow the tissues to ‘talk to each other’ and exchange metabolites that help the heart respond adequately to the damage caused by the heart attack.

This work provides novel insights into how spatially separated tissues with different embryonic origins can still coordinate after a heart attack. It also highlights how multi-tissue computational simulations can be used to unravel complex diseases. In future studies it will be critical to determine whether a similar multi-tissue crosstalk occurs in chronic heart attacks (which are more common), and if drugs that alter these molecular processes could improve the outcome for patients.

References

Article and author information

Author details

  1. Regan Odongo

    Regan Odongo is in the Department of Bioengineering, Gebze Technical University, Gebze, Kocaeli, Turkey

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7200-7477
  2. Tunahan Çakır

    Tunahan Çakır is in the Department of Bioengineering, Gebze Technical University, Gebze, Kocaeli, Turkey

    For correspondence
    tcakir@gtu.edu.tr
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8262-4420

Publication history

  1. Version of Record published: June 8, 2021 (version 1)

Copyright

© 2021, Odongo and Çakır

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 616
    Page views
  • 30
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Regan Odongo
  2. Tunahan Çakır
(2021)
Heart Attack: Working together
eLife 10:e69863.
https://doi.org/10.7554/eLife.69863

Further reading

    1. Computational and Systems Biology
    2. Plant Biology
    Ruth Großeholz, Friederike Wanke ... Klaus Harter
    Research Article Updated

    Brassinosteroids (BR) are key hormonal regulators of plant development. However, whereas the individual components of BR perception and signaling are well characterized experimentally, the question of how they can act and whether they are sufficient to carry out the critical function of cellular elongation remains open. Here, we combined computational modeling with quantitative cell physiology to understand the dynamics of the plasma membrane (PM)-localized BR response pathway during the initiation of cellular responses in the epidermis of the Arabidopsis root tip that are be linked to cell elongation. The model, consisting of ordinary differential equations, comprises the BR-induced hyperpolarization of the PM, the acidification of the apoplast and subsequent cell wall swelling. We demonstrate that the competence of the root epidermal cells for the BR response predominantly depends on the amount and activity of H+-ATPases in the PM. The model further predicts that an influx of cations is required to compensate for the shift of positive charges caused by the apoplastic acidification. A potassium channel was subsequently identified and experimentally characterized, fulfilling this function. Thus, we established the landscape of components and parameters for physiological processes potentially linked to cell elongation, a central process in plant development.

    1. Computational and Systems Biology
    Felix Proulx-Giraldeau, Jan M Skotheim, Paul François
    Research Article

    Cell size is controlled to be within a specific range to support physiological function. To control their size, cells use diverse mechanisms ranging from ‘sizers’, in which differences in cell size are compensated for in a single cell division cycle, to ‘adders’, in which a constant amount of cell growth occurs in each cell cycle. This diversity raises the question why a particular cell would implement one rather than another mechanism? To address this question, we performed a series of simulations evolving cell size control networks. The size control mechanism that evolved was influenced by both cell cycle structure and specific selection pressures. Moreover, evolved networks recapitulated known size control properties of naturally occurring networks. If the mechanism is based on a G1 size control and an S/G2/M timer, as found for budding yeast and some human cells, adders likely evolve. But, if the G1 phase is significantly longer than the S/G2/M phase, as is often the case in mammalian cells in vivo, sizers become more likely. Sizers also evolve when the cell cycle structure is inverted so that G1 is a timer, while S/G2/M performs size control, as is the case for the fission yeast S. pombe. For some size control networks, cell size consistently decreases in each cycle until a burst of cell cycle inhibitor drives an extended G1 phase much like the cell division cycle of the green algae Chlamydomonas. That these size control networks evolved such self-organized criticality shows how the evolution of complex systems can drive the emergence of critical processes.