Despite the Existence of Eight Isoforms of GPX Enzymes : A Part from the Book Chapter : Ferroptosis-Induced Metabolic Shifts in Cardiac Cells: Exploring the Influence of Glutaminolysis

Despite the existence of eight isoforms of GPX enzymes, early studies have identified the inhibition of the GPX4 isoform as the primary driver of ferroptosis. This is attributed to its capability to reduce various oxidized phospholipids, including phosphatidylethanolamine hydroperoxides, FA hydroperoxides, and cholesterol, which represent critical components implicated in the initiation and propagation of ferroptosis. GPX4 reduces the hydroperoxy-phospholipids to stable hydroxy-phospholipids at the expense of reduced glutathione (GSH), which is oxidized in the process. GSH is a tripeptide produced from cysteine, glycine, and glutamate in the cytoplasm. Cysteine is transported into cells via the antiporter system xc-, which facilitates the exchange of cystine, the oxidized form of cysteine, with glutamate in a 1:1 ratio. This transport system comprises two components: a light chain named xCT and a heavy chain known as 4F2 heavy chain (4F2hc), making it part of the family of heterodimeric amino acid transporters. Furthermore, studies have demonstrated that inhibiting either system xc- or GPX4 potently induces ferroptosis via cysteine deprivation, driving GSH depletion and ultimately impairing the cellular antioxidant defense mechanism. Inhibition of cysteine import and depletion of the cellular GSH pool by system xc- inhibitors (e.g., erastin) have been shown to impair GPX4 function, leading to ferroptosis. Another classic inducer of ferroptosis is the RAS-selective lethal 3 (RSL3), which promotes ferroptosis through the direct inhibition of GPX4 activity. Although recent studies have challenged the idea of RSL3 as a direct GPX4 inhibitor, demonstrating that the cytosolic adaptor protein, 14-3-3ε is required for RSL3 to exert its inhibitory effect on GPX4 activity. This highlights the complex yet important role of RSL3 as a ferroptotic inducer.

Author(s) Details:

Keishla M. Rodríguez-Graciani
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.

Xavier R. Chapa-Dubocq
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.

Esteban J. Ayala-Arroyo
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.

Ivana Chaves-Negrón
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.

Sehwan Jang
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.

Nataliya Chorna
Department of Biochemistry, School of Medicine, University of Puerto Rico, San Juan, PR, USA.

Taber S. Maskrey
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.

Peter Wipf
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.

Sabzali Javadov
Department of Physiology, School of Medicine, University of Puerto Rico, San Juan, PR, USA.


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Recent Global Research Developments in The Role of Human Cardiac Stem Cells in Heart Regeneration

The Long and Winding Road to Cardiac Regeneration
This review discusses the challenges and progress in cardiac regeneration, focusing on the potential of human cardiac stem cells to repair and regenerate heart tissue after injury [1].

Cardiac Regeneration: the Heart of the Issue
This article reviews the regenerative capacity of the heart and the potential of cell therapies, including human cardiac stem cells, to promote heart regeneration following myocardial infarction [2].

Heart Regeneration: Beyond New Muscle and Vessels
This review explores the latest insights into heart regeneration, focusing on the roles of various cell types, including human cardiac stem cells, in promoting tissue repair and regeneration following heart injury [3].

Human Ventricular Progenitor Cells Promote the Formation of New Heart Tissue Following Heart Attack
This investigational study demonstrates that human ventricular progenitor cells can promote the regeneration of healthy cardiac tissue, improve cardiac function, and reduce scar tissue following a heart attack [4].

Cell Signalling in the Cardiovascular System: An Overview
This overview discusses the critical roles of cell signaling in the cardiovascular system, including its physiological and pathophysiological functions in maintaining cardiac function and promoting heart regeneration [5].

References

  1. Sacco, A. M., Castaldo, C., Di Meglio, F., Nurzynska, D., Palermi, S., Spera, R., Gnasso, R., Zinno, G., & Belviso, I. (2023). The Long and Winding Road to Cardiac Regeneration. Applied Sciences, 13(16), 9432. https://doi.org/10.3390/app13169432
  2. Carotenuto, F., Manzari, V., & Di Nardo, P. (2021). Cardiac Regeneration: the Heart of the Issue. Current Transplantation Reports, 8, 67-75. https://doi.org/10.1007/s40472-021-00319-0
  3. Sayers, J. R., & Riley, P. R. (2021). Heart Regeneration: Beyond New Muscle and Vessels. Cardiovascular Research, 117(3), 727-742. https://doi.org/10.1093/cvr/cvaa320
  4. AstraZeneca. (2022). Human Ventricular Progenitor Cells Promote the Formation of New Heart Tissue Following Heart Attack. Retrieved from https://www.astrazeneca.com/media-centre/press-releases/2022/human-ventricular-progenitor-cells-promote-formation-new-heart-tissue-following-heart-attack.html
  5. Wheeler-Jones, C. P. D. (2005). Cell Signalling in the Cardiovascular System: An Overview. Heart, 91(10), 1366. https://doi.org/10.1136/hrt.2005.072280

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